Bio

Academic Appointments


Administrative Appointments


  • Chair, Stanford University School of Medicine - Neurobiology (2008 - Present)

Research & Scholarship

Current Research and Scholarly Interests


THE MYSTERY AND MAGIC OF GLIA

We are interested in the development and function of glial cells in the mammalian central nervous system. To understand the interactions between neurons and glial cells we have developed methods to highly purify and culture retinal ganglion cells (neurons) as well as the glial cell types they interact with, oligodendrocytes and astrocytes, from the rodent optic nerve. We are using a large variety of methods to address these issues including cell purification by immunopanning, tissue culture, patch clamping, immunohistochemistry and molecular biology. Currently, we are focusing on several questions:

(1) What are the cell-cell interactions that control myelination and node of Ranvier formation?

(2) Do glial cells play a role in synapse formation and function?

(3) What are the signals that promote the survival and growth of retinal ganglion cells and can we use this knowledge to promote their survival and regeneration after injury?

(4) How do protoplasmic astrocytes, the main glial cell type in gray matter, develop and what is their function?.

We have found evidence of several novel glial signals that induce the onset of myelination, the clustering of axonal sodium channels, the survival and growth of retinal ganglion cells, and the formation of synapses. We are characterizing these processes and are attempting to identify these glial-derived molecules.

Teaching

2013-14 Courses


Publications

Journal Articles


  • Intrinsic and extrinsic control of oligodendrocyte development. Current opinion in neurobiology Zuchero, J. B., Barres, B. A. 2013; 23 (6): 914-920

    Abstract

    Oligodendrocytes (OLs) are the myelinating glia of the central nervous system. Myelin is essential for the rapid propagation of action potentials as well as for metabolic support of axons, and its loss in demyelinating diseases like multiple sclerosis has profound pathological consequences. The many steps in the development of OLs - from the specification of oligodendrocyte precursor cells (OPCs) during embryonic development to their differentiation into OLs that myelinate axons - are under tight regulation. Here we discuss recent advances in understanding how these steps of OL development are controlled intrinsically by transcription factors and chromatin remodeling and extrinsically by signaling molecules and neuronal activity. We also discuss how knowledge of these pathways is now allowing us to take steps toward generating patient-specific OPCs for disease modeling and myelin repair.

    View details for DOI 10.1016/j.conb.2013.06.005

    View details for PubMedID 23831087

  • Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain. Nature cell biology Rafalski, V. A., Ho, P. P., Brett, J. O., Ucar, D., Dugas, J. C., Pollina, E. A., Chow, L. M., Ibrahim, A., Baker, S. J., Barres, B. A., Steinman, L., Brunet, A. 2013; 15 (6): 614-624

    Abstract

    Oligodendrocytes-the myelin-forming cells of the central nervous system-can be regenerated during adulthood. In adults, new oligodendrocytes originate from oligodendrocyte progenitor cells (OPCs), but also from neural stem cells (NSCs). Although several factors supporting oligodendrocyte production have been characterized, the mechanisms underlying the generation of adult oligodendrocytes are largely unknown. Here we show that genetic inactivation of SIRT1, a protein deacetylase implicated in energy metabolism, increases the production of new OPCs in the adult mouse brain, in part by acting in NSCs. New OPCs produced following SIRT1 inactivation differentiate normally, generating fully myelinating oligodendrocytes. Remarkably, SIRT1 inactivation ameliorates remyelination and delays paralysis in mouse models of demyelinating injuries. SIRT1 inactivation leads to the upregulation of genes involved in cell metabolism and growth factor signalling, in particular PDGF receptor ? (PDGFR?). Oligodendrocyte expansion following SIRT1 inactivation is mediated at least in part by AKT and p38 MAPK-signalling molecules downstream of PDGFR?. The identification of drug-targetable enzymes that regulate oligodendrocyte regeneration in adults could facilitate the development of therapies for demyelinating injuries and diseases, such as multiple sclerosis.

    View details for DOI 10.1038/ncb2735

    View details for PubMedID 23644469

  • Generation of oligodendroglial cells by direct lineage conversion. Nature biotechnology Yang, N., Zuchero, J. B., Ahlenius, H., Marro, S., Ng, Y. H., Vierbuchen, T., Hawkins, J. S., Geissler, R., Barres, B. A., Wernig, M. 2013; 31 (5): 434-439

    Abstract

    Transplantation of oligodendrocyte precursor cells (OPCs) is a promising potential therapeutic strategy for diseases affecting myelin. However, the derivation of engraftable OPCs from human pluripotent stem cells has proven difficult and primary OPCs are not readily available. Here we report the generation of induced OPCs (iOPCs) by direct lineage conversion. Forced expression of the three transcription factors Sox10, Olig2 and Zfp536 was sufficient to reprogram mouse and rat fibroblasts into iOPCs with morphologies and gene expression signatures resembling primary OPCs. More importantly, iOPCs gave rise to mature oligodendrocytes that could ensheath multiple host axons when co-cultured with primary dorsal root ganglion cells and formed myelin after transplantation into shiverer mice. We propose direct lineage reprogramming as a viable alternative approach for the generation of OPCs for use in disease modeling and regenerative medicine.

    View details for DOI 10.1038/nbt.2564

    View details for PubMedID 23584610

  • Emerging roles of astrocytes in neural circuit development NATURE REVIEWS NEUROSCIENCE Clarke, L. E., Barres, B. A. 2013; 14 (5): 311-321

    Abstract

    Astrocytes are now emerging as key participants in many aspects of brain development, function and disease. In particular, new evidence shows that astrocytes powerfully control the formation, maturation, function and elimination of synapses through various secreted and contact-mediated signals. Astrocytes are also increasingly being implicated in the pathophysiology of many psychiatric and neurological disorders that result from synaptic defects. A better understanding of how astrocytes regulate neural circuit development and function in the healthy and diseased brain might lead to the development of therapeutic agents to treat these diseases.

    View details for DOI 10.1038/nrn3484

    View details for Web of Science ID 000317913900008

    View details for PubMedID 23595014

  • Glia as primary drivers of neuropathology in TDP-43 proteinopathies PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Sloan, S. A., Barres, B. A. 2013; 110 (12): 4439-4440

    View details for DOI 10.1073/pnas.1301608110

    View details for Web of Science ID 000317521600018

    View details for PubMedID 23471990

  • Glia Keep Synapse Distribution under Wraps. Cell Clarke, L. E., Barres, B. A. 2013; 154 (2): 267-8

    Abstract

    The wiring of the nervous system requires that axons navigate to the correct targets and maintain their correct positions during developmental growth. In this issue, Shao et al. (2013) now reveal a crucial new role for glia in preserving correct synaptic connectivity during developmental growth.

    View details for PubMedID 23870116

  • Thrombospondin-4 Contributes to Spinal Sensitization and Neuropathic Pain States JOURNAL OF NEUROSCIENCE Kim, D., Li, K., Boroujerdi, A., Yu, Y. P., Zhou, C., Deng, P., Park, J., Zhang, X., Lee, J., Corpe, M., Sharp, K., Steward, O., Eroglu, C., Barres, B., Zaucke, F., Xu, Z. C., Luo, Z. D. 2012; 32 (26): 8977-8987

    Abstract

    Neuropathic pain is a common cause of pain after nerve injury, but its molecular basis is poorly understood. In a post-gene chip microarray effort to identify new target genes contributing to neuropathic pain development, we report here the characterization of a novel neuropathic pain contributor, thrombospondin-4 (TSP4), using a neuropathic pain model of spinal nerve ligation injury. TSP4 is mainly expressed in astrocytes and significantly upregulated in the injury side of dorsal spinal cord that correlates with the development of neuropathic pain states. TSP4 blockade by intrathecal antibodies, antisense oligodeoxynucleotides, or inactivation of the TSP4 gene reverses or prevents behavioral hypersensitivities. Intrathecal injection of TSP4 protein into naive rats is sufficient to enhance the frequency of EPSCs in spinal dorsal horn neurons, suggesting an increased excitatory presynaptic input, and to cause similar behavioral hypersensitivities. Together, these findings support that injury-induced spinal TSP4 may contribute to spinal presynaptic hypersensitivity and neuropathic pain states. Development of TSP4 antagonists has the therapeutic potential for target-specific neuropathic pain management.

    View details for DOI 10.1523/JNEUROSCI.6494-11.2012

    View details for Web of Science ID 000305890700021

    View details for PubMedID 22745497

  • Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors NATURE Allen, N. J., Bennett, M. L., Foo, L. C., Wang, G. X., Chakraborty, C., Smith, S. J., Barres, B. A. 2012; 486 (7403): 410-?

    Abstract

    In the developing central nervous system (CNS), the control of synapse number and function is critical to the formation of neural circuits. We previously demonstrated that astrocyte-secreted factors powerfully induce the formation of functional excitatory synapses between CNS neurons. Astrocyte-secreted thrombospondins induce the formation of structural synapses, but these synapses are postsynaptically silent. Here we use biochemical fractionation of astrocyte-conditioned medium to identify glypican 4 (Gpc4) and glypican 6 (Gpc6) as astrocyte-secreted signals sufficient to induce functional synapses between purified retinal ganglion cell neurons, and show that depletion of these molecules from astrocyte-conditioned medium significantly reduces its ability to induce postsynaptic activity. Application of Gpc4 to purified neurons is sufficient to increase the frequency and amplitude of glutamatergic synaptic events. This is achieved by increasing the surface level and clustering, but not overall cellular protein level, of the GluA1 subunit of the AMPA (?-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) glutamate receptor (AMPAR). Gpc4 and Gpc6 are expressed by astrocytes in vivo in the developing CNS, with Gpc4 expression enriched in the hippocampus and Gpc6 enriched in the cerebellum. Finally, we demonstrate that Gpc4-deficient mice have defective synapse formation, with decreased amplitude of excitatory synaptic currents in the developing hippocampus and reduced recruitment of AMPARs to synapses. These data identify glypicans as a family of novel astrocyte-derived molecules that are necessary and sufficient to promote glutamate receptor clustering and receptivity and to induce the formation of postsynaptically functioning CNS synapses.

    View details for DOI 10.1038/nature11059

    View details for Web of Science ID 000305466800045

    View details for PubMedID 22722203

  • The role of glial cells in synapse elimination CURRENT OPINION IN NEUROBIOLOGY Chung, W., Barres, B. A. 2012; 22 (3): 438-445

    Abstract

    Excessive synapses generated during early development are eliminated extensively to form functionally mature neural circuits. Synapses in juvenile and mature brains are highly dynamic, and undergo remodeling processes through constant formation and elimination of dendritic spines. Although neural activity has been implicated in initiating the synapse elimination process cell-autonomously, the cellular and molecular mechanisms that transduce changes in correlated neural activity into structural changes in synapses are largely unknown. Recently, however, new findings provide evidence that in different species, glial cells, non-neuronal cell types in the nervous system are crucial in eliminating neural debris and unwanted synapses through phagocytosis. Glial cells not only clear fragmented axons and synaptic debris produced during synapse elimination, but also engulf unwanted synapses thereby actively promoting synapse elimination non-cell autonomously. These new findings support the important role of glial cells in the formation and maintenance of functional neural circuits in development as well as in adult stages and neurodegenerative diseases.

    View details for DOI 10.1016/j.conb.2011.10.003

    View details for Web of Science ID 000306634700011

    View details for PubMedID 22036016

  • Genomic Analysis of Reactive Astrogliosis JOURNAL OF NEUROSCIENCE Zamanian, J. L., Xu, L., Foo, L. C., Nouri, N., Zhou, L., Giffard, R. G., Barres, B. A. 2012; 32 (18): 6391-6410

    Abstract

    Reactive astrogliosis is characterized by a profound change in astrocyte phenotype in response to all CNS injuries and diseases. To better understand the reactive astrocyte state, we used Affymetrix GeneChip arrays to profile gene expression in populations of reactive astrocytes isolated at various time points after induction using two mouse injury models, ischemic stroke and neuroinflammation. We find reactive gliosis consists of a rapid, but quickly attenuated, induction of gene expression after insult and identify induced Lcn2 and Serpina3n as strong markers of reactive astrocytes. Strikingly, reactive astrocyte phenotype strongly depended on the type of inducing injury. Although there is a core set of genes that is upregulated in reactive astrocytes from both injury models, at least 50% of the altered gene expression is specific to a given injury type. Reactive astrocytes in ischemia exhibited a molecular phenotype that suggests that they may be beneficial or protective, whereas reactive astrocytes induced by LPS exhibited a phenotype that suggests that they may be detrimental. These findings demonstrate that, despite well established commonalities, astrocyte reactive gliosis is a highly heterogeneous state in which astrocyte activities are altered to respond to the specific injury. This raises the question of how many subtypes of reactive astrocytes exist. Our findings provide transcriptome databases for two subtypes of reactive astrocytes that will be highly useful in generating new and testable hypotheses of their function, as well as for providing new markers to detect different types of reactive astrocytes in human neurological diseases.

    View details for DOI 10.1523/JNEUROSCI.6221-11.2012

    View details for Web of Science ID 000303598900032

    View details for PubMedID 22553043

  • Axon Degeneration: Where the Wld(s) Things Are CURRENT BIOLOGY Wang, J. T., Barres, B. A. 2012; 22 (7): R221-R223

    Abstract

    Expression of the Wld(s) protein significantly delays axon degeneration in injuries and diseases, but the mechanism for this protection is unknown. Two recent reports present evidence that axonal mitochondria are required for Wld(S)-mediated axon protection.

    View details for DOI 10.1016/j.cub.2012.02.056

    View details for Web of Science ID 000302844900006

    View details for PubMedID 22497934

  • A novel role for microglia in minimizing excitotoxicity BMC BIOLOGY Howe, M. L., Barres, B. A. 2012; 10

    Abstract

    Microglia are the abundant, resident myeloid cells of the central nervous system (CNS) that become rapidly activated in response to injury or inflammation. While most studies of microglia focus on this phenomenon, little is known about the function of 'resting' microglia, which possess fine, branching cellular processes. Biber and colleagues, in a recent paper in Journal of Neuroinflammation, report that ramified microglia can limit excitotoxicity, an important insight for understanding mechanisms that limit neuron death in CNS disease.

    View details for DOI 10.1186/1741-7007-10-7

    View details for Web of Science ID 000299827700002

    View details for PubMedID 22293401

  • A Nogo signal coordinates the perfect match between myelin and axons PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Scholze, A. R., Barres, B. A. 2012; 109 (4): 1003-1004

    View details for DOI 10.1073/pnas.1120301109

    View details for Web of Science ID 000299412600009

    View details for PubMedID 22308525

  • Axon degeneration: Molecular mechanisms of a self-destruction pathway JOURNAL OF CELL BIOLOGY Wang, J. T., Medress, Z. A., Barres, B. A. 2012; 196 (1): 7-18

    Abstract

    Axon degeneration is a characteristic event in many neurodegenerative conditions including stroke, glaucoma, and motor neuropathies. However, the molecular pathways that regulate this process remain unclear. Axon loss in chronic neurodegenerative diseases share many morphological features with those in acute injuries, and expression of the Wallerian degeneration slow (WldS) transgene delays nerve degeneration in both events, indicating a common mechanism of axonal self-destruction in traumatic injuries and degenerative diseases. A proposed model of axon degeneration is that nerve insults lead to impaired delivery or expression of a local axonal survival factor, which results in increased intra-axonal calcium levels and calcium-dependent cytoskeletal breakdown.

    View details for DOI 10.1083/jcb.201108111

    View details for Web of Science ID 000299269000003

    View details for PubMedID 22232700

  • The Complement System: An Unexpected Role in Synaptic Pruning During Development and Disease ANNUAL REVIEW OF NEUROSCIENCE, VOL 35 Stephan, A. H., Barres, B. A., Stevens, B. 2012; 35: 369-389

    Abstract

    An unexpected role for the classical complement cascade in the elimination of central nervous system (CNS) synapses has recently been discovered. Complement proteins are localized to developing CNS synapses during periods of active synapse elimination and are required for normal brain wiring. The function of complement proteins in the brain appears analogous to their function in the immune system: clearance of cellular material that has been tagged for elimination. Similarly, synapses tagged with complement proteins may be eliminated by microglial cells expressing complement receptors. In addition, developing astrocytes release signals that induce the expression of complement components in the CNS. In the mature brain, early synapse loss is a hallmark of several neurodegenerative diseases. Complement proteins are profoundly upregulated in many CNS diseases prior to signs of neuron loss, suggesting a reactivation of similar developmental mechanisms of complement-mediated synapse elimination potentially driving disease progression.

    View details for DOI 10.1146/annurev-neuro-061010-113810

    View details for Web of Science ID 000307960400019

    View details for PubMedID 22715882

  • Between the sheets: a molecular sieve makes myelin membranes. Developmental cell Zuchero, J. B., Barres, B. A. 2011; 21 (3): 385-386

    Abstract

    Myelin is a lipid-rich, spiraled membrane structure that allows for rapid propagation of action potentials through axons. In this issue, Aggarwal et al. (2011) present evidence that myelin basic protein, essential for myelination by oligodendrocytes, regulates the biosynthesis of myelin membranes by restricting diffusion of membrane-bound proteins into compact myelin.

    View details for DOI 10.1016/j.devcel.2011.08.023

    View details for PubMedID 21920305

  • Development of a Method for the Purification and Culture of Rodent Astrocytes NEURON Foo, L. C., Allen, N. J., Bushong, E. A., Ventura, P. B., Chung, W., Zhou, L., Cahoy, J. D., Daneman, R., Zong, H., Ellisman, M. H., Barres, B. A. 2011; 71 (5): 799-811

    Abstract

    The inability to purify and culture astrocytes has long hindered studies of their function. Whereas astrocyte progenitor cells can be cultured from neonatal brain, culture of mature astrocytes from postnatal brain has not been possible. Here, we report a new method to prospectively purify astrocytes by immunopanning. These astrocytes undergo apoptosis in culture, but vascular cells and HBEGF promote their survival in serum-free culture. We found that some developing astrocytes normally undergo apoptosis in vivo and that the vast majority of astrocytes contact blood vessels, suggesting that astrocytes are matched to blood vessels by competing for vascular-derived trophic factors such as HBEGF. Compared to traditional astrocyte cultures, the gene profiles of the cultured purified postnatal astrocytes much more closely resemble those of in vivo astrocytes. Although these astrocytes strongly promote synapse formation and function, they do not secrete glutamate in response to stimulation.

    View details for DOI 10.1016/j.neuron.2011.07.022

    View details for Web of Science ID 000294877900006

    View details for PubMedID 21903074

  • Transgenic Mice Reveal Unexpected Diversity of On-Off Direction-Selective Retinal Ganglion Cell Subtypes and Brain Structures Involved in Motion Processing JOURNAL OF NEUROSCIENCE Rivlin-Etzion, M., Zhou, K., Wei, W., Elstrott, J., Nguyen, P. L., Barres, B. A., Huberman, A. D., Feller, M. B. 2011; 31 (24): 8760-8769

    Abstract

    On-Off direction-selective retinal ganglion cells (DSGCs) encode the axis of visual motion. They respond strongly to an object moving in a preferred direction and weakly to an object moving in the opposite, "null," direction. Historically, On-Off DSGCs were classified into four subtypes according to their directional preference (anterior, posterior, superior, or inferior). Here, we compare two genetically identified populations of On-Off DSGCs: dopamine receptor 4 (DRD4)-DSGCs and thyrotropin-releasing hormone receptor (TRHR)-DSGCs. We find that although both populations are tuned for posterior motion, they can be distinguished by a variety of physiological and anatomical criteria. First, the directional tuning of TRHR-DSGCs is broader than that of DRD4-DSGCs. Second, whereas both populations project similarly to the dorsal lateral geniculate nucleus, they project differently to the ventral lateral geniculate nucleus and the superior colliculus. Moreover, TRHR-DSGCs, but not DRD4-DSGCs, also project to the zona incerta, a thalamic area not previously known to receive direction-tuned visual information. Our findings reveal unexpected diversity among mouse On-Off DSGC subtypes that uniquely process and convey image motion to the brain.

    View details for DOI 10.1523/JNEUROSCI.0564-11.2011

    View details for Web of Science ID 000291642800009

    View details for PubMedID 21677160

  • The Lipid Sulfatide Is a Novel Myelin-Associated Inhibitor of CNS Axon Outgrowth JOURNAL OF NEUROSCIENCE Winzeler, A. M., Mandemakers, W. J., Sun, M. Z., Stafford, M., Phillips, C. T., Barres, B. A. 2011; 31 (17): 6481-6492

    Abstract

    CNS myelin is strongly inhibitory to growing axons and is thought to be a major contributor to CNS axon regenerative failure. Although a number of proteins present in myelin, including Nogo, MAG, and oligodendrocyte-myelin glycoprotein (OMgp), have been identified as myelin-associated inhibitors, studies of mice lacking these genes suggest that additional inhibitors present in CNS myelin remain to be identified. Here we have investigated the hypothesis that myelin lipids contribute to CNS regenerative failure. We identified sulfatide, a major constituent of CNS myelin, as a novel myelin-associated inhibitor of neurite outgrowth. Sulfatide, but not galactocerebroside or ceramide, strongly inhibited the neurite outgrowth of retinal ganglion cells (RGCs) when used as a purified lipid substrate. The mechanism involved in sulfatide-mediated inhibition may share features with other known inhibitors, because the Rho inhibitor C3 transferase lessened these effects. Myelin in which sulfatide was lacking or blocked using specific antibodies was significantly less inhibitory to RGC neurite outgrowth in vitro than was wild-type myelin, indicating that sulfatide is a major component of the inhibitory activity of CNS myelin. Mice unable to make sulfatide did not regenerate RGC axons more robustly after optic nerve crush than wild-type littermates under normal conditions but did exhibit a small but significant enhancement in the extent of zymosan-induced regeneration. These results demonstrate that specific lipids can powerfully inhibit axon growth, identify sulfatide as a novel myelin-associated axon growth inhibitor, and provide evidence that sulfatide inhibition contributes to axon regenerative failure in vivo.

    View details for DOI 10.1523/JNEUROSCI.3004-10.2011

    View details for Web of Science ID 000289934600025

    View details for PubMedID 21525289

  • The Down Syndrome Critical Region Regulates Retinogeniculate Refinement JOURNAL OF NEUROSCIENCE Blank, M., Fuerst, P. G., Stevens, B., Nouri, N., Kirkby, L., Warrier, D., Barres, B. A., Feller, M. B., Huberman, A. D., Burgess, R. W., Garner, C. C. 2011; 31 (15): 5764-5776

    Abstract

    Down syndrome (DS) is a developmental disorder caused by a third chromosome 21 in humans (Trisomy 21), leading to neurological deficits and cognitive impairment. Studies in mouse models of DS suggest that cognitive deficits in the adult are associated with deficits in synaptic learning and memory mechanisms, but it is unclear whether alterations in the early wiring and refinement of neuronal circuits contribute to these deficits. Here, we show that early developmental refinement of visual circuits is perturbed in mouse models of Down syndrome. Specifically, we find excessive eye-specific segregation of retinal axons in the dorsal lateral geniculate nucleus. Indeed, the degree of refinement scales with defects in the "Down syndrome critical region" (DSCR) in a dose-dependent manner. We further identify Dscam (Down syndrome cell adhesion molecule), a gene within the DSCR, as a regulator of eye-specific segregation of retinogeniculate projections. Although Dscam is not the sole gene in the DSCR contributing to enhanced refinement in trisomy, Dscam dosage clearly regulates cell spacing and dendritic fasciculation in a specific class of retinal ganglion cells. Thus, altered developmental refinement of visual circuits that occurs before sensory experience is likely to contribute to visual impairment in individuals with Down syndrome.

    View details for DOI 10.1523/JNEUROSCI.6015-10.2011

    View details for Web of Science ID 000289472400026

    View details for PubMedID 21490218

  • Emergence of Lamina-Specific Retinal Ganglion Cell Connectivity by Axon Arbor Retraction and Synapse Elimination JOURNAL OF NEUROSCIENCE Cheng, T., Liu, X., Faulkner, R. L., Stephan, A. H., Barres, B. A., Huberman, A. D., Cheng, H. 2010; 30 (48): 16376-16382

    Abstract

    Throughout the nervous system, neurons restrict their connections to specific depths or "layers" of their targets to constrain the type and number of synapses they make. Despite the importance of lamina-specific synaptic connectivity, the mechanisms that give rise to this feature in mammals remain poorly understood. Here we examined the cellular events underlying the formation of lamina-specific retinal ganglion cell (RGC) axonal projections to the superior colliculus (SC) of the mouse. By combining a genetically encoded marker of a defined RGC subtype (OFF-?RGCs) with serial immunoelectron microscopy, we resolved the ultrastructure of axon terminals fated for laminar stabilization versus those fated for removal. We found that OFF-?RGCs form synapses across the full depth of the retinorecipient SC before undergoing lamina-specific arbor retraction and synapse elimination to arrive at their mature, restricted pattern of connectivity. Interestingly, we did not observe evidence of axon degeneration or glia-induced synapse engulfment during this process. These findings indicate that lamina-specific visual connections are generated through the selective stabilization of correctly targeted axon arbors and suggest that the decision to maintain or eliminate an axonal projection reflects the molecular compatibility of presynaptic and postsynaptic neurons at a given laminar depth.

    View details for DOI 10.1523/JNEUROSCI.3455-10.2010

    View details for Web of Science ID 000284999900031

    View details for PubMedID 21123583

  • The Mouse Blood-Brain Barrier Transcriptome: A New Resource for Understanding the Development and Function of Brain Endothelial Cells PLOS ONE Daneman, R., Zhou, L., Agalliu, D., Cahoy, J. D., Kaushal, A., Barres, B. A. 2010; 5 (10)

    Abstract

    The blood-brain barrier (BBB) maintains brain homeostasis and limits the entry of toxins and pathogens into the brain. Despite its importance, little is known about the molecular mechanisms regulating the development and function of this crucial barrier. In this study we have developed methods to highly purify and gene profile endothelial cells from different tissues, and by comparing the transcriptional profile of brain endothelial cells with those purified from the liver and lung, we have generated a comprehensive resource of transcripts that are enriched in the BBB forming endothelial cells of the brain. Through this comparison we have identified novel tight junction proteins, transporters, metabolic enzymes, signaling components, and unknown transcripts whose expression is enriched in central nervous system (CNS) endothelial cells. This analysis has identified that RXRalpha signaling cascade is specifically enriched at the BBB, implicating this pathway in regulating this vital barrier. This dataset provides a resource for understanding CNS endothelial cells and their interaction with neural and hematogenous cells.

    View details for DOI 10.1371/journal.pone.0013741

    View details for Web of Science ID 000283645300021

    View details for PubMedID 21060791

  • Astrocyte heterogeneity: an underappreciated topic in neurobiology CURRENT OPINION IN NEUROBIOLOGY Zhang, Y., Barres, B. A. 2010; 20 (5): 588-594

    Abstract

    Astrocytes, one of the most numerous types of cells in the central nervous system, are crucial for potassium homeostasis, neurotransmitter uptake, synapse formation, regulation of blood-brain-barrier, and the development of the nervous system. Historically, astrocytes have been studied as a homogeneous group of cells. However, evidence has accumulated that suggests heterogeneity of astrocytes across brain regions as well as within the same brain regions. Astrocytes differ in their morphology, developmental origin, gene expression profile, physiological properties, function, and response to injury and disease. A better understanding of the heterogeneity of astrocytes will greatly aid investigation of the function of astrocytes in normal brain as well as the roles of astrocytes in neurological disorders.

    View details for DOI 10.1016/j.conb.2010.06.005

    View details for Web of Science ID 000283481100010

    View details for PubMedID 20655735

  • Endogenous antibodies promote rapid myelin clearance and effective axon regeneration after nerve injury PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Vargas, M. E., Watanabe, J., Singh, S. J., Robinson, W. H., Barres, B. A. 2010; 107 (26): 11993-11998

    Abstract

    Degenerating myelin inhibits axon regeneration and is rapidly cleared after peripheral (PNS) but not central nervous system (CNS) injury. To better understand mechanisms underlying rapid PNS myelin clearance, we tested the potential role of the humoral immune system. Here, we show that endogenous antibodies are required for rapid and robust PNS myelin clearance and axon regeneration. B-cell knockout JHD mice display a significant delay in macrophage influx, myelin clearance, and axon regeneration. Rapid clearance of myelin debris is restored in mutant JHD mice by passive transfer of antibodies from naďve WT mice or by an anti-PNS myelin antibody, but not by delivery of nonneural antibodies. We demonstrate that degenerating nerve tissue is targeted by preexisting endogenous antibodies that control myelin clearance by promoting macrophage entrance and phagocytic activity. These results demonstrate a role for immunoglobulin (Ig) in clearing damaged self during healing and suggest that the immune-privileged status of the CNS may contribute to failure of CNS myelin clearance and axon regeneration after injury.

    View details for DOI 10.1073/pnas.1001948107

    View details for Web of Science ID 000279332300061

    View details for PubMedID 20547838

  • Enhanced synaptic connectivity and epilepsy in C1q knockout mice PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Chu, Y., Jin, X., Parada, I., Pesic, A., Stevens, B., Barres, B., Prince, D. A. 2010; 107 (17): 7975-7980

    Abstract

    Excessive CNS synapses are eliminated during development to establish mature patterns of neuronal connectivity. A complement cascade protein, C1q, is involved in this process. Mice deficient in C1q fail to refine retinogeniculate connections resulting in excessive retinal innervation of lateral geniculate neurons. We hypothesized that C1q knockout (KO) mice would exhibit defects in neocortical synapse elimination resulting in enhanced excitatory synaptic connectivity and epileptiform activity. We recorded spontaneous and evoked field potential activity in neocortical slices and obtained video-EEG recordings from implanted C1q KO and wild-type (WT) mice. We also used laser scanning photostimulation of caged glutamate and whole cell recordings to map excitatory and inhibitory synaptic connectivity. Spontaneous and evoked epileptiform field potentials occurred at multiple sites in neocortical slices from C1q KO, but not WT mice. Laser mapping experiments in C1q KO slices showed that the proportion of glutamate uncaging sites from which excitatory postsynaptic currents (EPSCs) could be evoked ("hotspot ratio") increased significantly in layer IV and layer V, although EPSC amplitudes were unaltered. Density of axonal boutons was significantly increased in layer V pyramidal neurons of C1q KO mice. Implanted KO mice had frequent behavioral seizures consisting of behavioral arrest associated with bihemispheric spikes and slow wave activity lasting from 5 to 30 s. Results indicate that epileptogenesis in C1q KO mice is related to a genetically determined failure to prune excessive excitatory synapses during development.

    View details for DOI 10.1073/pnas.0913449107

    View details for Web of Science ID 000277088700067

    View details for PubMedID 20375278

  • Dicer1 and miR-219 Are Required for Normal Oligodendrocyte Differentiation and Myelination NEURON Dugas, J. C., Cuellar, T. L., Scholze, A., Ason, B., Ibrahim, A., Emery, B., Zamanian, J. L., Foo, L. C., McManus, M. T., Barres, B. A. 2010; 65 (5): 597-611

    Abstract

    To investigate the role of microRNAs in regulating oligodendrocyte (OL) differentiation and myelination, we utilized transgenic mice in which microRNA processing was disrupted in OL precursor cells (OPCs) and OLs by targeted deletion of Dicer1. We found that inhibition of OPC-OL miRNA processing disrupts normal CNS myelination and that OPCs lacking mature miRNAs fail to differentiate normally in vitro. We identified three miRNAs (miR-219, miR-138, and miR-338) that are induced 10-100x during OL differentiation; the most strongly induced of these, miR-219, is necessary and sufficient to promote OL differentiation, and partially rescues OL differentiation defects caused by total miRNA loss. miR-219 directly represses the expression of PDGFRalpha, Sox6, FoxJ3, and ZFP238 proteins, all of which normally help to promote OPC proliferation. Together, these findings show that miR-219 plays a critical role in coupling differentiation to proliferation arrest in the OL lineage, enabling the rapid transition from proliferating OPCs to myelinating OLs.

    View details for DOI 10.1016/j.neuron.2010.01.027

    View details for Web of Science ID 000275758000005

    View details for PubMedID 20223197

  • Gabapentin Receptor alpha 2 delta-1 Is a Neuronal Thrombospondin Receptor Responsible for Excitatory CNS Synaptogenesis CELL Eroglu, C., Allen, N. J., Susman, M. W., O'Rourke, N. A., Park, C. Y., Oezkan, E., Chakraborty, C., Mulinyawe, S. B., Annis, D. S., Huberman, A. D., Green, E. M., Lawler, J., Dolmetsch, R., Garcia, K. C., Smith, S. J., Luo, Z. D., Rosenthal, A., Mosher, D. F., Barres, B. A. 2009; 139 (2): 380-392

    Abstract

    Synapses are asymmetric cellular adhesions that are critical for nervous system development and function, but the mechanisms that induce their formation are not well understood. We have previously identified thrombospondin as an astrocyte-secreted protein that promotes central nervous system (CNS) synaptogenesis. Here, we identify the neuronal thrombospondin receptor involved in CNS synapse formation as alpha2delta-1, the receptor for the anti-epileptic and analgesic drug gabapentin. We show that the VWF-A domain of alpha2delta-1 interacts with the epidermal growth factor-like repeats common to all thrombospondins. alpha2delta-1 overexpression increases synaptogenesis in vitro and in vivo and is required postsynaptically for thrombospondin- and astrocyte-induced synapse formation in vitro. Gabapentin antagonizes thrombospondin binding to alpha2delta-1 and powerfully inhibits excitatory synapse formation in vitro and in vivo. These findings identify alpha2delta-1 as a receptor involved in excitatory synapse formation and suggest that gabapentin may function therapeutically by blocking new synapse formation.

    View details for DOI 10.1016/j.cell.2009.09.025

    View details for Web of Science ID 000270857500020

    View details for PubMedID 19818485

  • Selective Remodeling: Refining Neural Connectivity at the Neuromuscular Junction PLOS BIOLOGY Chung, W., Barres, B. A. 2009; 7 (8)

    Abstract

    A primer on new research by Fuentes-Medel and colleagues explains the important role of non-neural cells in clearing neural debris, which is continuously produced during the normal remodeling processes that establish and maintain neural connectivity.

    View details for DOI 10.1371/journal.pbio.1000185

    View details for Web of Science ID 000269226300004

    View details for PubMedID 19707269

  • Myelin Gene Regulatory Factor Is a Critical Transcriptional Regulator Required for CNS Myelination CELL Emery, B., Agalliu, D., Cahoy, J. D., Watkins, T. A., Dugas, J. C., Mulinyawe, S. B., Ibrahim, A., Ligon, K. L., Rowitch, D. H., Barres, B. A. 2009; 138 (1): 172-185

    Abstract

    The transcriptional control of CNS myelin gene expression is poorly understood. Here we identify gene model 98, which we have named myelin gene regulatory factor (MRF), as a transcriptional regulator required for CNS myelination. Within the CNS, MRF is specifically expressed by postmitotic oligodendrocytes. MRF is a nuclear protein containing an evolutionarily conserved DNA binding domain homologous to a yeast transcription factor. Knockdown of MRF in oligodendrocytes by RNA interference prevents expression of most CNS myelin genes; conversely, overexpression of MRF within cultured oligodendrocyte progenitors or the chick spinal cord promotes expression of myelin genes. In mice lacking MRF within the oligodendrocyte lineage, premyelinating oligodendrocytes are generated but display severe deficits in myelin gene expression and fail to myelinate. These mice display severe neurological abnormalities and die because of seizures during the third postnatal week. These findings establish MRF as a critical transcriptional regulator essential for oligodendrocyte maturation and CNS myelination.

    View details for DOI 10.1016/j.cell.2009.04.031

    View details for Web of Science ID 000267848600023

    View details for PubMedID 19596243

  • Genetic Identification of an On-Off Direction-Selective Retinal Ganglion Cell Subtype Reveals a Layer-Specific Subcortical Map of Posterior Motion NEURON Huberman, A. D., Wei, W., Elstrott, J., Stafford, B. K., Feller, M. B., Barres, B. A. 2009; 62 (3): 327-334

    Abstract

    Motion detection is an essential component of visual processing. On-Off direction-selective retinal ganglion cells (On-Off DSGCs) detect objects moving along specific axes of the visual field due to their precise retinal circuitry. The brain circuitry of On-Off DSGCs, however, is largely unknown. We report a mouse with GFP expressed selectively by the On-Off DSGCs that detect posterior motion (On-Off pDSGCs), allowing two-photon targeted recordings of their light responses and delineation of their complete map of central connections. On-Off pDSGCs project exclusively to the dorsal lateral geniculate nucleus and superior colliculus and in both targets form synaptic lamina that are separate from a lamina corresponding to non-DSGCs. Thus, individual On-Off DSGC subtypes are molecularly distinct and establish circuits that map specific qualities of directional motion to dedicated subcortical areas. This suggests that each RGC subtype represents a unique parallel pathway whose synaptic specificity in the retina is recapitulated in central targets.

    View details for DOI 10.1016/j.neuron.2009.04.014

    View details for Web of Science ID 000266146100005

    View details for PubMedID 19447089

  • Wnt/beta-catenin signaling is required for CNS, but not non-CNS, angiogenesis PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Daneman, R., Agalliu, D., Zhou, L., Kuhnert, F., Kuo, C. J., Barres, B. A. 2009; 106 (2): 641-646

    Abstract

    Despite the importance of CNS blood vessels, the molecular mechanisms that regulate CNS angiogenesis and blood-brain barrier (BBB) formation are largely unknown. Here we analyze the role of Wnt/beta-catenin signaling in regulating the formation of CNS blood vessels. First, through the analysis of TOP-Gal Wnt reporter mice, we identify that canonical Wnt/beta-catenin signaling is specifically activated in CNS, but not non-CNS, blood vessels during development. This activation correlates with the expression of different Wnt ligands by neural progenitor cells in distinct locations throughout the CNS, including Wnt7a and Wnt7b in ventral regions and Wnt1, Wnt3, Wnt3a, and Wnt4 in dorsal regions. Blockade of Wnt/beta-catenin signaling in vivo specifically disrupts CNS, but not non-CNS, angiogenesis. These defects include reduction in vessel number, loss of capillary beds, and the formation of hemorrhagic vascular malformations that remain adherent to the meninges. Furthermore, we demonstrate that Wnt/beta-catenin signaling regulates the expression of the BBB-specific glucose transporter glut-1. Taken together these experiments reveal an essential role for Wnt/beta-catenin signaling in driving CNS-specific angiogenesis and provide molecular evidence that angiogenesis and BBB formation are in part linked.

    View details for DOI 10.1073/pnas.0805165106

    View details for Web of Science ID 000262804000052

    View details for PubMedID 19129494

  • Distinct Stages of Myelination Regulated by gamma-Secretase and Astrocytes in a Rapidly Myelinating CNS Coculture System NEURON Watkins, T. A., Emery, B., Mulinyawe, S., Barres, B. A. 2008; 60 (4): 555-569

    Abstract

    Mechanistic studies of CNS myelination have been hindered by the lack of a rapidly myelinating culture system. Here, we describe a versatile CNS coculture method that allows time-lapse microscopy and molecular analysis of distinct stages of myelination. Employing a culture architecture of reaggregated neurons fosters extension of dense beds of axons from purified retinal ganglion cells. Seeding of oligodendrocyte precursor cells on these axons results in differentiation and ensheathment in as few as 3 days, with generation of compact myelin within 6 days. This technique enabled (1) the demonstration that oligodendrocytes initiate new myelin segments only during a brief window early in their differentiation, (2) identification of a contribution of astrocytes to the rate of myelin wrapping, and (3) molecular dissection of the role of oligodendrocyte gamma-secretase activity in controlling the ensheathment of axons. These insights illustrate the value of this defined system for investigating multiple aspects of CNS myelination.

    View details for DOI 10.1016/j.neuron.2008.09.011

    View details for Web of Science ID 000261603200007

    View details for PubMedID 19038214

  • Unlocking CNS Cell Type Heterogeneity CELL Emery, B., Barres, B. A. 2008; 135 (4): 596-598

    Abstract

    A major challenge to understanding how cells work together in the central nervous system (CNS) is the heterogeneous cellular composition of the brain. In this issue, Heiman et al. (2008) and Doyle et al. (2008) introduce a new strategy (TRAP) that enables the profiling of translated mRNAs in specific CNS cell populations without the need for purifying cells to homogeneity.

    View details for DOI 10.1016/j.cell.2008.10.031

    View details for Web of Science ID 000260886900010

    View details for PubMedID 19013270

  • The Mystery and Magic of Glia: A Perspective on Their Roles in Health and Disease NEURON Barres, B. A. 2008; 60 (3): 430-440

    Abstract

    In this perspective, I review recent evidence that glial cells are critical participants in every major aspect of brain development, function, and disease. Far more active than once thought, glial cells powerfully control synapse formation, function, and blood flow. They secrete many substances whose roles are not understood, and they are central players in CNS injury and disease. I argue that until the roles of nonneuronal cells are more fully understood and considered, neurobiology as a whole will progress only slowly.

    View details for DOI 10.1016/j.neuron.2008.10.013

    View details for Web of Science ID 000260983800014

    View details for PubMedID 18995817

  • Architecture and activity-mediated refinement of axonal projections from a mosaic of genetically identified retinal ganglion cells NEURON Huberman, A. D., Manu, M., Koch, S. M., Susman, M. W., Lutz, A. B., Ullian, E. M., Baccus, S. A., Barres, B. A. 2008; 59 (3): 425-438

    Abstract

    Our understanding of how mammalian sensory circuits are organized and develop has long been hindered by the lack of genetic markers of neurons with discrete functions. Here, we report a transgenic mouse selectively expressing GFP in a complete mosaic of transient OFF-alpha retinal ganglion cells (tOFF-alphaRGCs). This enabled us to relate the mosaic spacing, dendritic anatomy, and electrophysiology of these RGCs to their complete map of projections in the brain. We find that tOFF-alphaRGCs project exclusively to the superior colliculus (SC) and dorsal lateral geniculate nucleus and are restricted to a specific laminar depth within each of these targets. The axons of tOFF-alphaRGC are also organized into columns in the SC. Both laminar and columnar specificity develop through axon refinement. Disruption of cholinergic retinal waves prevents the emergence of columnar- but not laminar-specific tOFF-alphaRGC connections. Our findings reveal that in a genetically identified sensory map, spontaneous activity promotes synaptic specificity by segregating axons arising from RGCs of the same subtype.

    View details for DOI 10.1016/j.neuron.2008.07.018

    View details for Web of Science ID 000258565500011

    View details for PubMedID 18701068

  • A novel purification method for CNS projection neurons leads to the identification of brain vascular cells as a source of trophic support for corticospinal motor neurons JOURNAL OF NEUROSCIENCE Dugas, J. C., Mandemakers, W., Rogers, M., Ibrahim, A., Daneman, R., Barres, B. A. 2008; 28 (33): 8294-8305

    Abstract

    One of the difficulties in studying cellular interactions in the CNS is the lack of effective methods to purify specific neuronal populations of interest. We report the development of a novel purification scheme, cholera toxin beta (CTB) immunopanning, in which a particular CNS neuron population is selectively labeled via retrograde axonal transport of the cell-surface epitope CTB, and then purified via immobilization with anti-CTB antibody. We have demonstrated the usefulness and versatility of this method by purifying both retinal ganglion cells and corticospinal motor neurons (CSMNs). Genomic expression analyses of purified CSMNs revealed that they express significant levels of many receptors for growth factors produced by brain endothelial cells; three of these factors, CXCL12, pleiotrophin, and IGF2 significantly enhanced purified CSMN survival, similar to previously characterized CSMN trophic factors BDNF and IGF1. In addition, endothelial cell conditioned medium significantly promoted CSMN neurite outgrowth. These findings demonstrate a useful method for the purification of several different types of CNS projection neurons, which in principle should work in many mammalian species, and provide evidence that endothelial-derived factors may represent an overlooked source of trophic support for neurons in the brain.

    View details for DOI 10.1523/JNEUROSCI.2010-08.2008

    View details for Web of Science ID 000258423400018

    View details for PubMedID 18701692

  • A transcriptome database for astrocytes, neurons, and oligodendrocytes: A new resource for understanding brain development and function JOURNAL OF NEUROSCIENCE Cahoy, J. D., Emery, B., Kaushal, A., Foo, L. C., Zamanian, J. L., Christopherson, K. S., Xing, Y., Lubischer, J. L., Krieg, P. A., Krupenko, S. A., Thompson, W. J., Barres, B. A. 2008; 28 (1): 264-278

    Abstract

    Understanding the cell-cell interactions that control CNS development and function has long been limited by the lack of methods to cleanly separate neural cell types. Here we describe methods for the prospective isolation and purification of astrocytes, neurons, and oligodendrocytes from developing and mature mouse forebrain. We used FACS (fluorescent-activated cell sorting) to isolate astrocytes from transgenic mice that express enhanced green fluorescent protein (EGFP) under the control of an S100beta promoter. Using Affymetrix GeneChip Arrays, we then created a transcriptome database of the expression levels of >20,000 genes by gene profiling these three main CNS neural cell types at various postnatal ages between postnatal day 1 (P1) and P30. This database provides a detailed global characterization and comparison of the genes expressed by acutely isolated astrocytes, neurons, and oligodendrocytes. We found that Aldh1L1 is a highly specific antigenic marker for astrocytes with a substantially broader pattern of astrocyte expression than the traditional astrocyte marker GFAP. Astrocytes were enriched in specific metabolic and lipid synthetic pathways, as well as the draper/Megf10 and Mertk/integrin alpha(v)beta5 phagocytic pathways suggesting that astrocytes are professional phagocytes. Our findings call into question the concept of a "glial" cell class as the gene profiles of astrocytes and oligodendrocytes are as dissimilar to each other as they are to neurons. This transcriptome database of acutely isolated purified astrocytes, neurons, and oligodendrocytes provides a resource to the neuroscience community by providing improved cell-type-specific markers and for better understanding of neural development, function, and disease.

    View details for DOI 10.1523/JNEUROSCI.4178-07.2008

    View details for Web of Science ID 000252242900029

    View details for PubMedID 18171944

  • The classical complement cascade mediates CNS synapse elimination CELL Stevens, B., Allen, N. J., Vazquez, L. E., Howell, G. R., Christopherson, K. S., Nouri, N., Micheva, K. D., Mehalow, A. K., Huberman, A. D., Stafford, B., Sher, A., Litke, A. M., Lambris, J. D., Smith, S. J., John, S. W., Barres, B. A. 2007; 131 (6): 1164-1178

    Abstract

    During development, the formation of mature neural circuits requires the selective elimination of inappropriate synaptic connections. Here we show that C1q, the initiating protein in the classical complement cascade, is expressed by postnatal neurons in response to immature astrocytes and is localized to synapses throughout the postnatal CNS and retina. Mice deficient in complement protein C1q or the downstream complement protein C3 exhibit large sustained defects in CNS synapse elimination, as shown by the failure of anatomical refinement of retinogeniculate connections and the retention of excess retinal innervation by lateral geniculate neurons. Neuronal C1q is normally downregulated in the adult CNS; however, in a mouse model of glaucoma, C1q becomes upregulated and synaptically relocalized in the adult retina early in the disease. These findings support a model in which unwanted synapses are tagged by complement for elimination and suggest that complement-mediated synapse elimination may become aberrantly reactivated in neurodegenerative disease.

    View details for DOI 10.1016/j.cell.2007.10.036

    View details for Web of Science ID 000252217100023

    View details for PubMedID 18083105

  • Disease gene candidates revealed by expression profiling of retinal ganglion cell development JOURNAL OF NEUROSCIENCE Wang, J. T., Kunzevitzky, N. J., Dugas, J. C., Cameron, M., Barres, B. A., Goldberg, J. L. 2007; 27 (32): 8593-8603

    Abstract

    To what extent do postmitotic neurons regulate gene expression during development or after injury? We took advantage of our ability to highly purify retinal ganglion cells (RGCs) to profile their pattern of gene expression at 13 ages from embryonic day 17 through postnatal day 21. We found that a large proportion of RGC genes are regulated dramatically throughout their postmitotic development, although the genes regulated through development in vivo generally are not regulated similarly by RGCs allowed to age in vitro. Interestingly, we found that genes regulated by developing RGCs are not generally correlated with genes regulated in RGCs stimulated to regenerate their axons. We unexpectedly found three genes associated with glaucoma, optineurin, cochlin, and CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1), previously thought to be primarily expressed in the trabecular meshwork, which are highly expressed by RGCs and regulated through their development. We also identified several other RGC genes that are encoded by loci linked to glaucoma. The expression of glaucoma-linked genes by RGCs suggests that, at least in some cases, RGCs may be directly involved in glaucoma pathogenesis rather than indirectly involved in response to increased intraocular pressure. Consistent with this hypothesis, we found that CYP1B1 overexpression potentiates RGC survival.

    View details for DOI 10.1523/JNEUROSCI.4488-07.2007

    View details for Web of Science ID 000248708400013

    View details for PubMedID 17687037

  • A crucial role for p57(Kip2) in the intracellular timer that controls oligodendrocyte differentiation JOURNAL OF NEUROSCIENCE Dugas, J. C., Ibrahim, A., Barres, B. A. 2007; 27 (23): 6185-6196

    Abstract

    The intracellular molecular mechanism that controls the timing of oligodendrocyte differentiation remains unknown. Temple and Raff (1986) previously showed that an oligodendrocyte precursor cell (OPC) can divide a maximum of approximately eight times before its daughter cells simultaneously cease proliferating and differentiate into oligodendrocytes. They postulated that over time the level of an intracellular molecule might synchronously change in each daughter cell, ultimately reaching a level that prohibited additional proliferation. Here, we report the discovery of such a molecule, the cyclin-dependent kinase inhibitor p57(Kip2) (Cdkn1c). We show in vitro that all daughters of a clone of OPCs express similar levels of p57(Kip2), that p57(Kip2) levels increase over time in proliferating OPCs, and that p57(Kip2) levels regulate how many times an OPC can divide before differentiating. These findings reveal a novel part of the mechanism by which OPCs measure time and are likely to extend to similar timers in many other precursor cell types.

    View details for DOI 10.1523/JNEUROSCI.0628-07.2007

    View details for Web of Science ID 000247049300012

    View details for PubMedID 17553990

  • Why is Wallerian degeneration in the CNS so slow? ANNUAL REVIEW OF NEUROSCIENCE Vargas, M. E., Barres, B. A. 2007; 30: 153-179

    Abstract

    Wallerian degeneration (WD) is the set of molecular and cellular events by which degenerating axons and myelin are cleared after injury. Why WD is rapid and robust in the PNS but slow and incomplete in the CNS is a longstanding mystery. Here we review current work on the mechanisms of WD with an emphasis on deciphering this mystery and on understanding whether slow WD in the CNS could account for the failure of CNS axons to regenerate.

    View details for DOI 10.1146/annurev.neuro.30.051606.094354

    View details for Web of Science ID 000248735400007

    View details for PubMedID 17506644

  • Functional genomic analysis of oligodendrocyte differentiation JOURNAL OF NEUROSCIENCE Dugas, J. C., Tai, Y. C., Speed, T. P., Ngai, J., Barres, B. A. 2006; 26 (43): 10967-10983

    Abstract

    To better understand the molecular mechanisms governing oligodendrocyte (OL) differentiation, we have used gene profiling to quantitatively analyze gene expression in synchronously differentiating OLs generated from pure oligodendrocyte precursor cells in vitro. By comparing gene expression in these OLs to OLs generated in vivo, we discovered that the program of OL differentiation can progress normally in the absence of heterologous cell-cell interactions. In addition, we found that OL differentiation was unexpectedly prolonged and occurred in at least two sequential stages, each characterized by changes in distinct complements of transcription factors and myelin proteins. By disrupting the normal dynamic expression patterns of transcription factors regulated during OL differentiation, we demonstrated that these sequential stages of gene expression can be independently controlled. We also uncovered several genes previously uncharacterized in OLs that encode transmembrane, secreted, and cytoskeletal proteins that are as highly upregulated as myelin genes during OL differentiation. Last, by comparing genomic loci associated with inherited increased risk of multiple sclerosis (MS) to genes regulated during OL differentiation, we identified several new positional candidate genes that may contribute to MS susceptibility. These findings reveal a previously unexpected complexity to OL differentiation and suggest that an intrinsic program governs successive phases of OL differentiation as these cells extend and align their processes, ensheathe, and ultimately myelinate axons.

    View details for DOI 10.1523/JNEUROSCI.2572-06.2006

    View details for Web of Science ID 000241553900006

    View details for PubMedID 17065439

  • The blood-brain barrier - Lessons from moody flies CELL Daneman, R., Barres, B. A. 2005; 123 (1): 9-12

    Abstract

    Despite the importance of the blood-brain barrier (BBB), little is known about the molecular mechanisms that control its integrity. The identification of moody, a gene required for the formation and maintenance of the Drosophila BBB, provides new insight into how paracellular junctions are formed at the barrier. Meanwhile, moody also has been identified in a screen for fly mutants with altered sensitivity to cocaine, remarkably implicating the BBB in the physiological response to narcotics.

    View details for DOI 10.1016/j.cell.2005.09.017

    View details for Web of Science ID 000232536800004

    View details for PubMedID 16213208

  • Signaling between glia and neurons: focus on synaptic plasticity CURRENT OPINION IN NEUROBIOLOGY Allen, N. J., Barres, B. A. 2005; 15 (5): 542-548

    Abstract

    Glial cells are now emerging from the shadows cast by their more excitable CNS counterparts. Within the developing nervous system, astrocytes and Schwann cells actively help to promote synapse formation and function, and have even been implicated in synapse elimination. In the adult brain, astrocytes respond to synaptic activity by releasing transmitters that modulate synaptic activity. Thus, glia are active participants in brain function. Many questions remain about the identity of glial-neuronal signals and their significance.

    View details for DOI 10.1016/j.conb.2005.08.006

    View details for Web of Science ID 000232943500008

    View details for PubMedID 16144764

  • Axon regeneration: It's getting crowded at the gates of TROY CURRENT BIOLOGY Mandemakers, W. J., Barres, B. A. 2005; 15 (8): R302-R305

    Abstract

    A novel neuronal receptor complex that mediates myelin's inhibitory action on nerve fiber regeneration has at last been identified. This discovery could be an important step towards promoting nerve regeneration after stroke or spinal cord injury.

    View details for DOI 10.1016/j.cub.2005.04.002

    View details for Web of Science ID 000228936600013

    View details for PubMedID 15854897

  • Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis CELL Christopherson, K. S., Ullian, E. M., Stokes, C. C., Mullowney, C. E., Hell, J. W., Agah, A., Lawler, J., Mosher, D. F., Bornstein, P., Barres, B. A. 2005; 120 (3): 421-433

    Abstract

    The establishment of neural circuitry requires vast numbers of synapses to be generated during a specific window of brain development, but it is not known why the developing mammalian brain has a much greater capacity to generate new synapses than the adult brain. Here we report that immature but not mature astrocytes express thrombospondins (TSPs)-1 and -2 and that these TSPs promote CNS synaptogenesis in vitro and in vivo. TSPs induce ultrastructurally normal synapses that are presynaptically active but postsynaptically silent and work in concert with other, as yet unidentified, astrocyte-derived signals to produce functional synapses. These studies identify TSPs as CNS synaptogenic proteins, provide evidence that astrocytes are important contributors to synaptogenesis within the developing CNS, and suggest that TSP-1 and -2 act as a permissive switch that times CNS synaptogenesis by enabling neuronal molecules to assemble into synapses within a specific window of CNS development.

    View details for Web of Science ID 000227028900016

    View details for PubMedID 15707899

  • Role for glia in synaptogenesis GLIA Ullian, E. M., Christopherson, K. S., Barres, B. A. 2004; 47 (3): 209-216

    Abstract

    Nearly one-half of the cells in a human brain are astrocytes, but the function of these little cells remains a great mystery. Astrocytes form an intimate association with synapses throughout the adult CNS, where they help regulate ion and neurotransmitter concentrations. Recent in vitro studies, however, have found that astrocytes also exert powerful control over the number of CNS synapses that form, are essential for postsynaptic function, and are required for synaptic stability and maintenance. Moreover, recent studies increasingly implicate astrocytes in vivo as participants in activity-dependent structural and functional synaptic changes throughout the nervous system. Taken together, these data force us to rethink the role of glia. We propose that astrocytes should not be viewed primarily as support cells, but rather as cells that actively control the structural and functional plasticity of synapses in developing and adult organisms.

    View details for DOI 10.1002/glia.20082

    View details for Web of Science ID 000223034500002

    View details for PubMedID 15252809

  • Invulnerability of retinal ganglion cells to NMDA excitotoxicity MOLECULAR AND CELLULAR NEUROSCIENCE Ullian, E. M., Barkis, W. B., Chen, S., Diamond, J. S., Barres, B. A. 2004; 26 (4): 544-557

    Abstract

    NMDA excitotoxicity has been proposed to mediate the death of retinal ganglion cells (RGCs) in glaucoma and ischemia. Here, we reexamine the effects of glutamate and NMDA on rat RGCs in vitro and in situ. We show that highly purified RGCs express NR1 and NR2 receptor subunits by Western blotting and immunostaining, and functional NMDA receptor channels by whole-cell patch-clamp recording. Nevertheless, high concentrations of glutamate or NMDA failed to induce the death of purified RGCs, even after prolonged exposure for 24 h. RGCs co-cultured together with ephrins, astrocytes, or mixed retinal cells were similarly invulnerable to glutamate and NMDA, though their NMDA currents were 4-fold larger. In contrast, even a short exposure to glutamate or NMDA induced the rapid and profound excitotoxic death of most hippocampal neurons in culture. To determine whether RGCs in an intact retina are vulnerable to excitotoxicity, we retrogradely labeled RGCs in vivo using fluorogold and exposed acutely isolated intact retinas to high concentrations of glutamate or NMDA. This produced a substantial and rapid loss of amacrine cells; however, RGCs were not affected. Nonetheless, RGCs expressed NMDA currents in situ that were larger than those reported for amacrine cells. Interestingly, the NMDA receptors expressed by RGCs were extrasynaptically localized both in vitro and in situ. These results indicate that RGCs in vitro and in situ are relatively invulnerable to glutamate and NMDA excitotoxicity compared to amacrine cells, and indicate that important, as yet unidentified, determinants downstream of NMDA receptors control vulnerability to excitotoxicity.

    View details for DOI 10.1016/j.mcn.2004.05.002

    View details for Web of Science ID 000223192700006

    View details for PubMedID 15276156

  • NGF controls axonal receptivity to myelination by Schwann cells or oligodendrocytes NEURON Chan, J. R., Watkins, T. A., Cosgaya, J. M., Zhang, C. Z., Chen, L., Reichardt, L. F., Shooter, E. M., Barres, B. A. 2004; 43 (2): 183-191

    Abstract

    Axons dictate whether or not they will become myelinated in both the central and peripheral nervous systems by providing signals that direct the development of myelinating glia. Here we identify the neurotrophin nerve growth factor (NGF) as a potent regulator of the axonal signals that control myelination of TrkA-expressing dorsal root ganglion neurons (DRGs). Unexpectedly, these NGF-regulated axonal signals have opposite effects on peripheral and central myelination, promoting myelination by Schwann cells but reducing myelination by oligodendrocytes. These findings indicate a novel role for growth factors in regulating the receptivity of axons to myelination and reveal that different axonal signals control central and peripheral myelination.

    View details for Web of Science ID 000222905400008

    View details for PubMedID 15260955

  • An oligodendrocyte lineage-specific semaphorin, sema5A, inhibits axon growth by retinal ganglion cells JOURNAL OF NEUROSCIENCE Goldberg, J. L., Vargas, M. E., Wang, J. T., Mandemakers, W., Oster, S. F., Sretavan, D. W., Barres, B. A. 2004; 24 (21): 4989-4999

    Abstract

    In the mammalian CNS, glial cells repel axons during development and inhibit axon regeneration after injury. It is unknown whether the same repulsive axon guidance molecules expressed by glia and their precursors during development also play a role in inhibiting regeneration in the injured CNS. Here we investigate whether optic nerve glial cells express semaphorin family members and, if so, whether these semaphorins inhibit axon growth by retinal ganglion cells (RGCs). We show that each optic nerve glial cell type, astrocytes, oligodendrocytes, and their precursor cells, expressed a distinct complement of semaphorins. One of these, sema5A, was expressed only by purified oligodendrocytes and their precursors, but not by astrocytes, and was present in both normal and axotomized optic nerve but not in peripheral nerves. Sema5A induced collapse of RGC growth cones and inhibited RGC axon growth when presented as a substrate in vitro. To determine whether sema5A might contribute to inhibition of axon growth after injury, we studied the ability of RGCs to extend axons when cultured on postnatal day (P) 4, P8, and adult optic nerve explants and found that axon growth was strongly inhibited. Blocking sema5A using a neutralizing antibody significantly increased RGC axon growth on these optic nerve explants. These data support the hypothesis that sema5A expression by oligodendrocyte lineage cells contributes to the glial cues that inhibit CNS regeneration.

    View details for DOI 10.1523/JNEUROSCI.4390-03.2004

    View details for Web of Science ID 000221654400011

    View details for PubMedID 15163691

  • Schwann cells and astrocytes induce synapse formation by spinal motor neurons in culture MOLECULAR AND CELLULAR NEUROSCIENCE Ullian, E. M., Harris, B. T., Wu, A., Chan, J. R., Barres, B. A. 2004; 25 (2): 241-251

    Abstract

    Glia constitute 90% of cells in the human nervous system, but relatively little is known about their functions. We have been focusing on the potential synaptic roles of glia in the CNS. We recently found that astrocytes increase the number of mature, functional synapses on retinal ganglion cells (RGCs) by sevenfold and are required for synaptic maintenance in vitro. These observations raised the question of whether glia similarly enhance synapse formation by other neuron types. Here we have investigated whether highly purified motor neurons isolated from developing rat spinal cords are able to form synapses in the absence of glia or whether glia similarly enhance synapse number. We show that spinal motor neurons (SMNs) form few synapses unless Schwann cells or astrocytes are present. Schwann cells increase the number of functional synapses by ninefold as measured by immunostaining, and increase spontaneous synaptic activity by several hundredfold. Surprisingly, the synapses formed between spinal motor neurons were primarily glutamatergic, as they could be blocked by CNQX. This synapse-promoting activity is not mediated by direct glial-neuronal cell contact but rather is mediated by secreted molecule(s) from the Schwann cells, as we previously found for astrocytes. Interestingly, the synapse-promoting activity from astrocytes and Schwann cells was functionally similar: Schwann cells also promoted synapse formation between retinal ganglion cells, and astrocytes promoted synapse formation between spinal motor neurons. These studies show that both astrocytes and Schwann cells strongly promote synapse formation between spinal motor neurons and demonstrate that glial regulation of synaptogenesis extends to other neuron types.

    View details for DOI 10.1016/j.mcn.2003.10.011

    View details for Web of Science ID 000220333300005

    View details for PubMedID 15019941

  • Inhibition of retinal ganglion cell regeneration by oligodendrocyte derived semaphorin 5A J. NEUROSCI Goldberg J, Vargas M, Mandemakers W, Barres BA 2004; 24: 4989-99
  • Importance of intrinsic mechanisms in cell fate decisions in the developing rat retina NEURON Cayouette, M., Barres, B. A., Raff, M. 2003; 40 (5): 897-904

    Abstract

    Cell diversification in the developing nervous system is thought to involve both cell-intrinsic mechanisms and extracellular signals, but their relative importance in particular cell fate decisions remains uncertain. In the mammalian retina, different cell types develop on a predictable schedule from multipotent retinal neuroepithelial cells (RNECs). A current view is that RNECs pass through a series of competence states, progressively changing their responsiveness to instructive extracellular cues, which also change over time. We show here, however, that embryonic day 16-17 (E16-17) rat RNECs develop similarly in serum-free clonal-density cultures and in serum-containing retinal explants--in the number of times they divide, the cell types they generate, and the order in which they generate these cell types. These surprising results suggest that extracellular signals may be less important than currently believed in determining when RNECs stop dividing and what cell types they generate when they withdraw from the cell cycle, at least from E16-17 onward.

    View details for Web of Science ID 000187042200007

    View details for PubMedID 14659089

  • What is a glial cell? GLIA Barres, B. A. 2003; 43 (1): 4-5

    View details for DOI 10.1002/glia.10252

    View details for Web of Science ID 000183682000002

    View details for PubMedID 12761860

  • Nerve regeneration: Regrowth stumped by shared receptor CURRENT BIOLOGY Watkins, T. A., Barres, B. A. 2002; 12 (19): R654-R656

    Abstract

    Three different myelin proteins, Nogo, MAG, and OMgp, inhibit regenerating axons after CNS injury. New work reveals that they all share a common receptor and that blockade of this receptor promotes CNS repair and functional recovery.

    View details for Web of Science ID 000178404100008

    View details for PubMedID 12361584

  • Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells SCIENCE Goldberg, J. L., Klassen, M. P., Hua, Y., Barres, B. A. 2002; 296 (5574): 1860-1864

    Abstract

    The central nervous system (CNS) loses the ability to regenerate early during development, but it is not known why. The retina has long served as a simple model system for study of CNS regeneration. Here we show that amacrine cells signal neonatal rat retinal ganglion cells (RGCs) to undergo a profound and apparently irreversible loss of intrinsic axon growth ability. Concurrently, retinal maturation triggers RGCs to greatly increase their dendritic growth ability. These results suggest that adult CNS neurons fail to regenerate not only because of CNS glial inhibition but also because of a loss of intrinsic axon growth ability.

    View details for Web of Science ID 000176054300047

    View details for PubMedID 12052959

  • Retinal ganglion cells do not extend axons by default: Promotion by neurotrophic signaling and electrical activity NEURON Goldberg, J. L., Espinosa, J. S., Xu, Y. F., Davidson, N., Kovacs, G. T., Barres, B. A. 2002; 33 (5): 689-702

    Abstract

    We investigate the signaling mechanisms that induce retinal ganglion cell (RGC) axon elongation by asking whether surviving neurons extend axons by default. We show that bcl-2 overexpression is sufficient to keep purified RGCs alive in the absence of any glial or trophic support. The bcl-2-expressing RGCs do not extend axons or dendrites unless signaled to do so by single peptide trophic factors. Axon growth stimulated by peptide trophic factors is remarkably slow but is profoundly potentiated by physiological levels of electrical activity spontaneously generated within embryonic explants or mimicked on a multielectrode silicon chip. These findings demonstrate that these surviving neurons do not constitutively extend axons and provide insight into the signals that may be necessary to promote CNS regeneration.

    View details for Web of Science ID 000174286200006

    View details for PubMedID 11879647

  • An Irreversible, Neonatal Switch from Axonal to Dendritic Growth in the Developing CNS. SCIENCE Goldberg, J., R. Daneman, Y. Hua, BA Barres 2002; 296: 1860-4
  • Neurobiology - Cholesterol - Making or breaking the synapse SCIENCE Barres, B. A., Smith, S. J. 2001; 294 (5545): 1296-1297

    View details for Web of Science ID 000172130200035

    View details for PubMedID 11701918

  • Differential control of clustering of the sodium channels Na(v)1.2 and Na(v)1.6 at developing CNS nodes of ranvier NEURON Kaplan, M. R., Cho, M. H., Ullian, E. M., Isom, L. L., Levinson, S. R., Barres, B. A. 2001; 30 (1): 105-119

    Abstract

    Na(v)1.6 is the main sodium channel isoform at adult nodes of Ranvier. Here, we show that Na(v)1.2 and its beta2 subunit, but not Na(v)1.6 or beta1, are clustered in developing central nervous system nodes and that clustering of Na(v)1.2 and Na(v)1.6 is differentially controlled. Oligodendrocyte-conditioned medium is sufficient to induce clustering of Na(v)1.2 alpha and beta2 subunits along central nervous system axons in vitro. This clustering is regulated by electrical activity and requires an intact actin cytoskeleton and synthesis of a non-sodium channel protein. Neither soluble- or contact-mediated glial signals induce clustering of Na(v)1.6 or beta1 in a nonmyelinating culture system. These data reveal that the sequential clustering of Na(v)1.2 and Na(v)1.6 channels is differentially controlled and suggest that myelination induces Na(v)1.6 clustering.

    View details for Web of Science ID 000168412900014

    View details for PubMedID 11343648

  • A role for the helix-loop-helix protein Id2 in the control of oligodendrocyte development NEURON Wang, S. L., Sdrulla, A., Johnson, J. E., Yokota, Y., Barres, B. A. 2001; 29 (3): 603-614

    Abstract

    Compared to neurons, the intracellular mechanisms that control glial differentiation are still poorly understood. We show here that oligodendrocyte lineage cells express the helix-loop-helix proteins Mash1 and Id2. Although Mash1 has been found to regulate neuronal development, we found that in the absence of Mash1 oligodendrocyte differentiation occurs normally. In contrast, we found that overexpression of Id2 powerfully inhibits oligodendrocyte differentiation, that Id2 normally translocates out of the nucleus at the onset of differentiation, and that absence of Id2 induces premature oligodendrocyte differentiation in vitro. These findings demonstrate that Id2 is a component of the intracellular mechanism that times oligodendrocyte differentiation and point to the existence of an as yet unidentified MyoD-like bHLH protein necessary for oligodendrocyte differentiation.

    View details for Web of Science ID 000167868900011

    View details for PubMedID 11301021

  • Induction of astrocyte differentiation by endothelial cells JOURNAL OF NEUROSCIENCE Mi, H. Y., Haeberle, H., Barres, B. A. 2001; 21 (5): 1538-1547

    Abstract

    Here we have investigated the mechanisms that control astrocyte differentiation within the developing rat optic nerve. Astrocytes are normally generated by astrocyte precursor cells within the embryonic optic nerve. We show that there is a close temporal and spatial correlation between endothelial and astrocyte differentiation. We tested the potential role of endothelial cells in inducing astrocyte differentiation by developing an immunopanning method to highly purify endothelial cells from developing optic nerves. We show that the purified endothelial cells, but not other embryonic optic nerve cell types, strongly induce the differentiation of purified astrocyte precursor cells into astrocytes in vitro. Leukemia inhibitory factor (LIF) and LIF receptors have been implicated previously in astrocyte differentiation in vivo. We show that purified endothelial cells express LIF mRNA and that their ability to induce astrocyte differentiation is prevented by a neutralizing anti-LIF, but not anti-ciliary neurotrophic factor, antiserum. These findings demonstrate a role for endothelial cells in inducing astrocyte differentiation. The induction of astrocyte differentiation by endothelial cells makes sense phylogenetically, anatomically, and functionally, because astrocytes evolved concurrently with brain vasculature and ensheathe capillaries throughout the brain. The ability to purify and culture astrocytes and endothelial cells should provide an excellent model system for future studies of blood-brain barrier development.

    View details for Web of Science ID 000167129700016

    View details for PubMedID 11222644

  • Control of synapse number by glia SCIENCE Ullian, E. M., Sapperstein, S. K., Christopherson, K. S., Barres, B. A. 2001; 291 (5504): 657-661

    Abstract

    Although astrocytes constitute nearly half of the cells in our brain, their function is a long-standing neurobiological mystery. Here we show by quantal analyses, FM1-43 imaging, immunostaining, and electron microscopy that few synapses form in the absence of glial cells and that the few synapses that do form are functionally immature. Astrocytes increase the number of mature, functional synapses on central nervous system (CNS) neurons by sevenfold and are required for synaptic maintenance in vitro. We also show that most synapses are generated concurrently with the development of glia in vivo. These data demonstrate a previously unknown function for glia in inducing and stabilizing CNS synapses, show that CNS synapse number can be profoundly regulated by nonneuronal signals, and raise the possibility that glia may actively participate in synaptic plasticity.

    View details for Web of Science ID 000166616000045

    View details for PubMedID 11158678

  • Neuronal and glial cell biology CURRENT OPINION IN NEUROBIOLOGY Barres, B. A., Barde, Y. A. 2000; 10 (5): 642-648

    Abstract

    Here, we review progress in our understanding of neuronal and glial cell biology during the past ten years, with an emphasis on glial cell fate specification, apoptosis, the cytoskeleton, neuronal polarity, synaptic vesicle recycling and targeting, regulation of the cytoskeleton by extracellular signals, and neuron-glia interactions.

    View details for Web of Science ID 000165302100015

    View details for PubMedID 11084327

  • Up a notch: Instructing gliogenesis NEURON Wang, S. L., Barres, B. A. 2000; 27 (2): 197-200

    View details for Web of Science ID 000088956000004

    View details for PubMedID 10985340

  • The relationship between neuronal survival and regeneration ANNUAL REVIEW OF NEUROSCIENCE Goldberg, J. L., Barres, B. A. 2000; 23: 579-612

    Abstract

    The ability of peripheral nervous system (PNS) but not central nervous system (CNS) neurons to regenerate their axons is a striking peculiarity of higher vertebrates. Much research has focused on the inhibitory signals produced by CNS glia that thwart regenerating axons. Less attention has been paid to the injury-induced loss of trophic stimuli needed to promote the survival and regeneration of axotomized neurons. Could differences in the mechanisms that control CNS and PNS neuronal survival and growth also contribute to the disparity in regenerative capacity? Here we review recent studies concerning the nature of the signals necessary to promote neuronal survival and growth, with an emphasis on their significance to regeneration after CNS injury.

    View details for Web of Science ID 000086730500020

    View details for PubMedID 10845076

  • Axonal control of oligodendrocyte development JOURNAL OF CELL BIOLOGY Barres, B. A., RAFF, M. C. 1999; 147 (6): 1123-1128

    View details for Web of Science ID 000084321000001

    View details for PubMedID 10601327

  • Astrocytes induce oligodendrocyte processes to align with and adhere to axons MOLECULAR AND CELLULAR NEUROSCIENCE Meyer-Franke, A., Shen, S. L., Barres, B. A. 1999; 14 (4-5): 385-397

    Abstract

    In order to study the signals that control the onset of myelination, we cocultured highly purified postnatal retinal ganglion cells and optic nerve oligodendrocytes under serum-free conditions that promote their survival for at least a month and found that no myelination occurred. Although the addition of optic nerve astrocytes induced the oligodendrocyte processes to align with, and adhere to, axons, myelination still did not occur. The effect of astrocytes was mimicked by removal of polysialic acid from both cell types using neuroaminidase. These findings provide evidence for a novel role for astrocytes in controlling the onset of myelination by promoting adhesion of oligodendrocyte processes to axons. They also suggest that other, as yet unidentified, cell-cell interactions are necessary to induce the myelination process itself.

    View details for Web of Science ID 000083403900010

    View details for PubMedID 10588392

  • A new role for glia: Generation of neurons! CELL Barres, B. A. 1999; 97 (6): 667-670

    View details for Web of Science ID 000080886300001

    View details for PubMedID 10380916

  • Purification and characterization of astrocyte precursor cells in the developing rat optic nerve JOURNAL OF NEUROSCIENCE Mi, H. Y., Barres, B. A. 1999; 19 (3): 1049-1061

    Abstract

    The signaling interactions that control oligodendrocyte generation from their precursor cells have been studied intensively. Much less is known about how astrocyte generation is normally controlled. Here we report the purification and characterization of astrocyte precursor cells (APCs) from the developing rat optic nerve. APCs are antigenically distinct from astrocytes. Both cell types are Pax2(+) and vimentin+, whereas astrocytes are GFAP+ and S100beta+, and the precursor cells are A2B5(+). In contrast to purified astrocytes, purified APCs rapidly die in serum-free culture but can be saved by basic fibroblast growth factor (bFGF) and glial growth factor 2 (GGF2). Unlike oligodendrocyte precursor cells, APCs do not differentiate by default; their differentiation into GFAP+ cells is induced by ciliary neurotrophic factor (CNTF) or by leukemia inhibitory factor (LIF). Finally, the survival, proliferation, and differentiation of APCs were promoted by coculture with other embryonic optic nerve cell types but not with purified embryonic retinal ganglion cells, indicating that interactions with non-neuronal cells are likely to play an important role in controlling astrocyte generation in the developing optic nerve.

    View details for Web of Science ID 000078285800019

    View details for PubMedID 9920668

  • The Schwann song of the glia-less synapse NEURON Ullian, E. M., Barres, T. A. 1998; 21 (4): 651-652

    View details for Web of Science ID 000076697300006

    View details for PubMedID 9808449

  • Cyclic AMP elevation is sufficient to promote the survival of spinal motor neurons in vitro JOURNAL OF NEUROSCIENCE Hanson, M. G., Shen, S. L., Wiemelt, A. P., McMorris, F. A., Barres, B. A. 1998; 18 (18): 7361-7371

    Abstract

    The short-term survival of highly purified embryonic spinal motor neurons (SMNs) in culture can be promoted by many peptide trophic factors, including brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), fibroblast growth factor (FGF), glial-derived neurotrophic factor (GDNF), and hepatocyte growth factor (HGF). We have asked whether these peptides are sufficient to promote the long-term survival of purified E15 SMNs. Contrary to previous reports, we find that when SMNs are cultured in serum-free medium containing a single peptide trophic factor only approximately one-third of the cells survive for 3 d in culture. When multiple factors are combined, additive effects on survival are observed transiently, but by 7 d of culture the majority of SMNs has died. Surprisingly, when cAMP levels are elevated, the majority of SMNs extend processes and survive for 1 week in culture in the absence of peptide trophic factors, even in low-density cultures. A combination of five peptide trophic factors, together with cAMP elevation, promotes the long-term survival of most of the SMNs in serum-free culture for 3 weeks. These findings provide useful culture conditions for studying the properties of SMNs and have implications for the treatment of motor neuron diseases.

    View details for Web of Science ID 000075893000029

    View details for PubMedID 9736656

  • Purification and characterization of adult oligodendrocyte precursor cells from the rat optic nerve JOURNAL OF NEUROSCIENCE Shi, J. Y., Marinovich, A., Barres, B. A. 1998; 18 (12): 4627-4636

    Abstract

    Oligodendrocyte precursor cells (OPCs) persist in substantial numbers in the adult brain in a quiescent state suggesting that they may provide a source of new oligodendrocytes after injury. To determine whether adult OPCs have the capacity to divide rapidly, we have developed a method to highly purify OPCs from adult optic nerve and have directly compared their properties with their perinatal counterparts. When cultured in platelet-derived growth factor (PDGF), an astrocyte-derived mitogen, perinatal OPCs divided approximately once per day, whereas adult OPCs divided only once every 3 or 4 d. The proliferation rate of adult OPCs was not increased by addition of fibroblast growth factor (FGF) or of the neuregulin glial growth factor 2 (GGF2), two mitogens that are normally produced by retinal ganglion cells. cAMP elevation has been shown previously to be essential for Schwann cells to survive and divide in response to GGF2 and other mitogens. Similarly we found that when cAMP levels were elevated, GGF2 alone was sufficient to induce perinatal OPCs to divide slowly, approximately once every 4 d, but adult OPCs still did not divide. When PDGF was combined with GGF2 and cAMP elevation, however, the adult OPCs began to divide rapidly. These findings indicate that adult OPCs are intrinsically different than perinatal OPCs. They are not senescent cells, however, because they retain the capacity to divide rapidly. Thus, after demyelinating injuries, enhanced axonal release of GGF2 or a related neuregulin might collaborate with astrocyte-derived PDGF to induce rapid division of adult OPCs.

    View details for Web of Science ID 000074068000018

    View details for PubMedID 9614237

  • Neural regeneration: Extending axons from bench to brain CURRENT BIOLOGY Goldberg, J. L., Barres, B. A. 1998; 8 (9): R310-R312

    Abstract

    Many studies have shown that myelin in the central nervous system strongly inhibits the regeneration of axons, so it comes as a surprise to discover that adult neurons transplanted into the brain rapidly extend their axons through myelinated pathways.

    View details for Web of Science ID 000073343100011

    View details for PubMedID 9560333

  • Retinal development: Communication helps you see the light CURRENT BIOLOGY WechslerReya, R. J., Barres, B. A. 1997; 7 (7): R433-R436

    Abstract

    Recent studies suggest that interactions between neurons, glial cells and endothelial cells are critical in determining the structure of the retina and the optic nerve. Dysregulation of these interactions can lead to disruption of retinal architecture and impairment of vision.

    View details for Web of Science ID A1997XK26500018

    View details for PubMedID 9210366

  • New views on synapse-glia interactions CURRENT OPINION IN NEUROBIOLOGY Pfrieger, F. W., Barres, B. A. 1996; 6 (5): 615-621

    Abstract

    Although glial cells ensheath synapses throughout the nervous system, the functional consequences of this relationship are uncertain. Recent studies suggest that glial cells may promote the formation of synapses and help to maintain their function by providing nerve terminals with energy substrates and glutamate precursors.

    View details for Web of Science ID A1996VR58600007

    View details for PubMedID 8937825

  • Ciliary neurotrophic factor enhances the rate of oligodendrocyte generation MOLECULAR AND CELLULAR NEUROSCIENCE Barres, B. A., BURNE, J. F., Holtmann, B., THOENEN, H., Sendtner, M., RAFF, M. C. 1996; 8 (2-3): 146-156

    Abstract

    Although ciliary neurotrophic factor (CNTF) is a potent survival factor for many types of neurons and glial cells in vitro, there is currently no evidence that it participates in normal development. Here we show that CNTF greatly enhances the rate of oligodendrocyte generation. Proliferation of oligodendrocyte precursor cells purified from rodent optic nerves and cultured in platelet-derived growth factor-containing medium is significantly increased by CNTF. Similarly, the number of proliferating oligodendrocyte precursor cells in developing optic nerves of transgenic mice lacking CNTF is decreased by up to threefold and the number of oligodendrocytes is transiently decreased; proliferation is restored to normal by the delivery of exogenous CNTF into the developing optic nerve. Both oligodendrocyte number and myelination ultimately attain wild-type values in CNTF-deficient adult mice, indicating that CNTF is not necessary for either oligodendrocyte differentiation or myelination, although it normally accelerates oligodendrocyte development by enhancing the proliferation of oligodendrocyte precursor cells.

    View details for Web of Science ID A1996VT00900009

    View details for PubMedID 8918831

  • Ciliary Neurotrophic Factor Enhances the Rate of Oligodendrocyte Generation Molecular and cellular neurosciences Barres, B. A., Burne, J. F., Holtmann, B., Thoenen, H., Sendtner, M., Raff, M. C. 1996; 8 (2/3): 146-56

    Abstract

    Although ciliary neurotrophic factor (CNTF) is a potent survival factor for many types of neurons and glial cells in vitro, there is currently no evidence that it participates in normal development. Here we show that CNTF greatly enhances the rate of oligodendrocyte generation. Proliferation of oligodendrocyte precursor cells purified from rodent optic nerves and cultured in platelet-derived growth factor-containing medium is significantly increased by CNTF. Similarly, the number of proliferating oligodendrocyte precursor cells in developing optic nerves of transgenic mice lacking CNTF is decreased by up to threefold and the number of oligodendrocytes is transiently decreased; proliferation is restored to normal by the delivery of exogenous CNTF into the developing optic nerve. Both oligodendrocyte number and myelination ultimately attain wild-type values in CNTF-deficient adult mice, indicating that CNTF is not necessary for either oligodendrocyte differentiation or myelination, although it normally accelerates oligodendrocyte development by enhancing the proliferation of oligodendrocyte precursor cells.

    View details for PubMedID 8954629

  • WHAT THE FLYS GLIA TELL THE FLYS BRAIN CELL Pfrieger, F. W., Barres, B. A. 1995; 83 (5): 671-674

    View details for Web of Science ID A1995TH94800002

    View details for PubMedID 8521482

  • CHARACTERIZATION OF THE SIGNALING INTERACTIONS THAT PROMOTE THE SURVIVAL AND GROWTH OF DEVELOPING RETINAL GANGLION-CELLS IN CULTURE NEURON MEYERFRANKE, A., Kaplan, M. R., Pfrieger, F. W., Barres, B. A. 1995; 15 (4): 805-819

    Abstract

    The signaling mechanisms that control the survival of CNS neurons are poorly understood. Here we show that, in contrast to PNS neurons, the survival of purified postnatal rat retinal ganglion cells (RGCs) in vitro is not promoted by peptide trophic factors unless their intracellular cAMP is increased pharmacologically or they are depolarized by K+ or glutamate agonists. Long-term survival of most RGCs in culture can be promoted by a combination of trophic factors normally produced along the visual pathway, including BDNF, CNTF, IGF1, an oligodendrocyte-derived protein, and forskolin. These results suggest that neurotransmitter stimulation and electrical activity enhance the survival of developing RGCs and raise the question of whether the survival control mechanisms of PNS and CNS neurons are different.

    View details for Web of Science ID A1995TC64000010

    View details for PubMedID 7576630

  • AXON MYELINATION - MYELINATION WITHOUT MYELIN-ASSOCIATED GLYCOPROTEIN CURRENT BIOLOGY MEYERFRANKE, A., Barres, B. 1994; 4 (9): 847-850

    Abstract

    Mice lacking myelin-associated glycoprotein surprisingly myelinate almost normally but their oligodendrocytes have lost their periaxonal cytoplasmic 'collars' and accidentally myelinate already-myelinated axons.

    View details for Web of Science ID A1994PH64100017

    View details for PubMedID 7529638

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