Spatiotemporal Control of CNS Myelination by Oligodendrocyte Programmed Cell Death through the TFEB-PUMA Axis.
Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing.
Nervous system function depends on proper myelination for insulation and critical trophic support for axons. Myelination is tightly regulated spatially and temporally, but how it is controlled molecularly remains largely unknown. Here, we identified key molecular mechanisms governing the regional and temporal specificity of CNS myelination. We show that transcription factor EB (TFEB) is highly expressed by differentiating oligodendrocytes and that its loss causes precocious and ectopic myelination in many parts of the murine brain. TFEB functions cell-autonomously through PUMA induction and Bax-Bak activation to promote programmed cell death of a subset of premyelinating oligodendrocytes, allowing selective elimination of oligodendrocytes in normally unmyelinated brain regions. This pathway is conserved across diverse brain areas and is critical for myelination timing. Our findings define an oligodendrocyte-intrinsic mechanism underlying the spatiotemporal specificity of CNS myelination, shedding light on how myelinating glia sculpt the nervous system during development.
View details for PubMedID 30503207
Glia Get Neurons in Shape.
2016; 165 (4): 775?76
Microglia are increasingly recognized for their major contributions during brain development and neurodegenerative disease. It is currently unknown whether these functions are carried out by subsets of microglia during different stages of development and adulthood or within specific brain regions. Here, we performed deep single-cell RNA sequencing (scRNA-seq) of microglia and related myeloid cells sorted from various regions of embryonic, early postnatal, and adult mouse brains. We found that the majority of adult microglia expressing homeostatic genes are remarkably similar in transcriptomes, regardless of brain region. By contrast, early postnatal microglia are more heterogeneous. We discovered a proliferative-region-associated microglia (PAM) subset, mainly found in developing white matter, that shares a characteristic gene signature with degenerative disease-associated microglia (DAM). Such PAM have amoeboid morphology, are metabolically active, and phagocytose newly formed oligodendrocytes. This scRNA-seq atlas will be a valuable resource for dissecting innate immune functions in health and disease.
View details for PubMedID 30606613
Functional Assembly of Accessory Optic System Circuitry Critical for Compensatory Eye Movements.
Glial cells are essential components of the nervous system. In this issue, Singhvi et al. uncover cellular and molecular mechanisms through which C. elegans glia shape sensory neuron terminals and thus control animal thermosensing behaviors.
View details for PubMedID 27153490
Dlg5 Regulates Dendritic Spine Formation and Synaptogenesis by Controlling Subcellular N-Cadherin Localization
JOURNAL OF NEUROSCIENCE
2014; 34 (38): 12745-12761
Cas Adaptor Proteins Organize the Retinal Ganglion Cell Layer Downstream of Integrin Signaling
2014; 81 (4): 779-786
Accurate motion detection requires neural circuitry that compensates for global visual field motion. Select subtypes of retinal ganglion cells perceive image motion and connect to the accessory optic system (AOS) in the brain, which generates compensatory eye movements that stabilize images during slow visual field motion. Here, we show that the murine transmembrane semaphorin 6A (Sema6A) is expressed in a subset of On direction-selective ganglion cells (On DSGCs) and is required for retinorecipient axonal targeting to the medial terminal nucleus (MTN) of the AOS. Plexin A2 and A4, two Sema6A binding partners, are expressed in MTN cells, attract Sema6A(+) On DSGC axons, and mediate MTN targeting of Sema6A(+) RGC projections. Furthermore, Sema6A/Plexin-A2/A4 signaling is required for the functional output of the AOS. These data reveal molecular mechanisms underlying the assembly of AOS circuits critical for moving image perception.
View details for DOI 10.1016/j.neuron.2015.03.064
View details for PubMedID 25959730
On and Off Retinal Circuit Assembly by Divergent Molecular Mechanisms
2013; 342 (6158): 590-?
Sema6B, Sema6C, and Sema6D Expression and Function during Mammalian Retinal Development
2013; 8 (4)
Stratification of retinal neuronal cell bodies and lamination of their processes provide a scaffold upon which neural circuits can be built. However, the molecular mechanisms that direct retinal ganglion cells (RGCs) to resolve into a single-cell retinal ganglion cell layer (GCL) are not well understood. The extracellular matrix protein laminin conveys spatial information that instructs the migration, process outgrowth, and reorganization of GCL cells. Here, we show that the ?1-Integrin laminin receptor is required for RGC positioning and reorganization into a single-cell GCL layer. ?1-Integrin signaling within migrating GCL cells requires Cas signaling-adaptor proteins, and in the absence of ?1-Integrin or Cas function retinal neurons form ectopic cell clusters beyond the inner-limiting membrane (ILM), phenocopying laminin mutants. These data reveal an essential role for Cas adaptor proteins in ?1-Integrin-mediated signaling events critical for the formation of the single-cell GCL in the mammalian retina.
View details for DOI 10.1016/j.neuron.2014.01.036
View details for Web of Science ID 000331464400009
View details for PubMedID 24559672
Guidance-Cue Control of Horizontal Cell Morphology, Lamination, and Synapse Formation in the Mammalian Outer Retina
JOURNAL OF NEUROSCIENCE
2012; 32 (20): 6859-6868
In the vertebrate retina, the formation of neural circuits within discrete laminae is critical for the establishment of retinal visual function. Precise formation of retinal circuits requires the coordinated actions of adhesive and repulsive molecules, including repulsive transmembrane semaphorins (Sema6A, Sema5A, and Sema5B). These semaphorins signal through different Plexin A (PlexA) receptors, thereby regulating distinct aspects of retinal circuit assembly. Here, we investigate the physiological roles of three Class 6 transmembrane semaphorins (Sema6B, Sema6C, and Sema6D), previously identified as PlexA receptor ligands in non-retinal tissues, in mammalian retinal development. We performed expression analysis and also phenotypic analyses of mice that carry null mutations in each of genes encoding these proteins using a broad range of inner and outer retinal markers. We find that these Class 6 semaphorins are uniquely expressed throughout postnatal retinal development in specific domains and cell types of the developing retina. However, we do not observe defects in stereotypical lamina-specific neurite stratification of retinal neuron subtypes in Sema6B-/- or Sema6C-/-; Sema6D-/- retinas. These findings indicate these Class 6 transmembrane semaphorins are unlikely to serve as major PlexA receptor ligands for the assembly of murine retinal circuit laminar organization.
View details for DOI 10.1371/journal.pone.0063207
View details for Web of Science ID 000319077300156
View details for PubMedID 23646199
Receptor-like tyrosine phosphatase PTP10D is required for long-term memory in Drosophila
JOURNAL OF NEUROSCIENCE
2007; 27 (16): 4396-4402
In the vertebrate retina, neuronal circuitry required for visual perception is organized within specific laminae. Photoreceptors convey external visual information to bipolar and horizontal cells at triad ribbon synapses established within the outer plexiform layer (OPL), initiating retinal visual processing. However, the molecular mechanisms that organize these three classes of neuronal processes within the OPL, thereby ensuring appropriate ribbon synapse formation, remain largely unknown. Here we show that mice with null mutations in Sema6A or PlexinA4 (PlexA4) exhibit a pronounced defect in OPL stratification of horizontal cell axons without any apparent deficits in bipolar cell dendrite or photoreceptor axon targeting. Furthermore, these mutant horizontal cells exhibit aberrant dendritic arborization and reduced dendritic self-avoidance within the OPL. Ultrastructural analysis shows that the horizontal cell contribution to rod ribbon synapse formation in PlexA4?/? retinas is disrupted. These findings define molecular components required for outer retina lamination and ribbon synapse formation.
View details for DOI 10.1523/JNEUROSCI.0267-12.2012
View details for Web of Science ID 000304419700012
View details for PubMedID 22593055
Tyrosine phosphorylation mediates multiple signal transduction pathways that play key roles in developmental processes and behavioral plasticity. The level of tyrosine phosphorylation is regulated by protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Extensive studies have investigated the roles of tyrosine kinases in memory formation. However, there were few studies on PTPs. To date, learning has been shown to be defective only for mouse knock-outs of PTPalpha, leukocyte common antigen-related, or PTPdelta. A major limitation of these studies arises from their inability to distinguish an acute (biochemical) impairment of memory formation from a more chronic abnormality in neurodevelopment. From a behavioral screen for defective long-term memory, we found chi mutants to disrupt expression of the PTP10D protein tyrosine phosphatase gene. We show that chi mutants are normal for learning, early memory, and anesthesia-resistant memory, whereas long-term memory specifically is abolished. Significantly, induction of a heat shock-PTP10D+ transgene before training fully rescues the memory defect of chi mutants, thereby demonstrating an acute role for PTP10D in behavioral plasticity. We show that PTP10D is widely expressed in the embryonic CNS and in the adult brain. Transgenic expression of upstream activating sequence-PTP10D+ in mushroom bodies is sufficient to rescue the memory defect of chi mutants. Our data clearly demonstrate that signaling through PTP10D in mushroom bodies is critical for the formation of long-term memory.
View details for DOI 10.1523/JNEUROSCI.4054-06.2007
View details for Web of Science ID 000245810200019
View details for PubMedID 17442824