Palmer Lab Select Publications

Professor of Neurosurgery, Emeritus

Publications

  • FOXP3+ regulatory T cells use heparanase to access IL-2 bound to ECM in inflamed tissues. bioRxiv : the preprint server for biology Martinez, H. A., Koliesnik, I., Kaber, G., Reid, J. K., Nagy, N., Barlow, G., Falk, B. A., Medina, C. O., Hargil, A., Vlodavsky, I., Li, J. P., Pérez-Cruz, M., Tang, S. W., Meyer, E. H., Wrenshall, L. E., Lord, J. D., Garcia, K. C., Palmer, T. D., Steinman, L., Nepom, G. T., Wight, T. N., Bollyky, P. L., Kuipers, H. F. 2023

    Abstract

    FOXP3+ regulatory T cells (Treg) depend on exogenous IL-2 for their survival and function, but circulating levels of IL-2 are low, making it unclear how Treg access this critical resource in vivo. Here, we show that Treg use heparanase (HPSE) to access IL-2 sequestered by heparan sulfate (HS) within the extracellular matrix (ECM) of inflamed central nervous system tissue. HPSE expression distinguishes human and murine Treg from conventional T cells and is regulated by the availability of IL-2. HPSE-/- Treg have impaired stability and function in vivo, including the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Conversely, endowing Treg with HPSE enhances their ability to access HS-sequestered IL-2 and their tolerogenic function in vivo. Together, these data identify novel roles for HPSE and the ECM in immune tolerance, providing new avenues for improving Treg-based therapy of autoimmunity.

    View details for DOI 10.1101/2023.02.26.529772

    View details for PubMedID 36909599

    View details for PubMedCentralID PMC10002643

  • Gestationally dependent immune organization at the maternal-fetal interface. Cell reports Moore, A. R., Vivanco Gonzalez, N., Plummer, K. A., Mitchel, O. R., Kaur, H., Rivera, M., Collica, B., Goldston, M., Filiz, F., Angelo, M., Palmer, T. D., Bendall, S. C. 2022; 41 (7): 111651

    Abstract

    The immune system and placenta have a dynamic relationship across gestation to accommodate fetal growth and development. High-resolution characterization of this maternal-fetal interface is necessary to better understand the immunology of pregnancy and its complications. We developed a single-cell framework to simultaneously immuno-phenotype circulating, endovascular, and tissue-resident cells at the maternal-fetal interface throughout gestation, discriminating maternal and fetal contributions. Our data reveal distinct immune profiles across the endovascular and tissue compartments with tractable dynamics throughout gestation that respond to a systemic immune challenge in a gestationally dependent manner. We uncover a significant role for the innate immune system where phagocytes and neutrophils drive temporal organization of the placenta through remarkably diverse populations, including PD-L1+ subsets having compartmental and early gestational bias. Our approach and accompanying datasets provide a resource for additional investigations into gestational immunology and evoke a more significant role for the innate immune system in establishing the microenvironment of early pregnancy.

    View details for DOI 10.1016/j.celrep.2022.111651

    View details for PubMedID 36384130

  • EXAMINING SEX-LINKED TRENDS IN THE PLACENTAL TRANSCRIPTOME DURING DEVELOPMENTAL WINDOW OF FETAL ANDROGEN PRODUCTION Braun, A., Muench, K., Palmer, T., Winn, V. W B SAUNDERS CO LTD. 2021: E31
  • Females Are Not Just 'Protected' Males: Sex-Specific Vulnerabilities in Placenta and Brain after Prenatal Immune Disruption. Braun, A. E., Carpentier, P. A., Babineau, B. A., Narayan, A. R., Kielhold, M. L., Moon, H., Su, J., Saravanapandian, V., Palmer, T. D. SPRINGER HEIDELBERG. 2021: 61A-62A
  • 16p11.2 microdeletion imparts transcriptional alterations in human iPSC-derived models of early neural development. eLife Roth, J. G., Muench, K. L., Asokan, A., Mallett, V. M., Gai, H., Verma, Y., Weber, S., Charlton, C., Fowler, J. L., Loh, K. M., Dolmetsch, R. E., Palmer, T. D. 2020; 9

    Abstract

    Microdeletions and microduplications of the 16p11.2 chromosomal locus are associated with syndromic neurodevelopmental disorders and reciprocal physiological conditions such as macro/microcephaly and high/low body mass index. To facilitate cellular and molecular investigations into these phenotypes, 65 clones of human induced pluripotent stem cells (hiPSCs) were generated from 13 individuals with 16p11.2 copy number variations (CNVs). To ensure these cell lines were suitable for downstream mechanistic investigations, a customizable bioinformatic strategy for the detection of random integration and expression of reprogramming vectors was developed and leveraged towards identifying a subset of 'footprint'-free hiPSC clones. Transcriptomic profiling of cortical neural progenitor cells derived from these hiPSCs identified alterations in gene expression patterns which precede morphological abnormalities reported at later neurodevelopmental stages. Interpreting clinical information-available with the cell lines by request from the Simons Foundation Autism Research Initiative-with this transcriptional data revealed disruptions in gene programs related to both nervous system function and cellular metabolism. As demonstrated by these analyses, this publicly available resource has the potential to serve as a powerful medium for probing the etiology of developmental disorders associated with 16p11.2 CNVs.

    View details for DOI 10.7554/eLife.58178

    View details for PubMedID 33169669

  • Examining Sex Differences in the Human Placental Transcriptome During the First Fetal Androgen Peak. Reproductive sciences (Thousand Oaks, Calif.) Braun, A. E., Muench, K. L., Robinson, B. G., Wang, A., Palmer, T. D., Winn, V. D. 2020

    Abstract

    Sex differences in human placenta exist from early pregnancy to term, however, it is unclear whether these differences are driven solely by sex chromosome complement or are subject to differential sex hormonal regulation. Here, we survey the human chorionic villus (CV) transcriptome for sex-linked signatures from 11 to 16 gestational weeks, corresponding to the first window of increasing testis-derived androgen production in male fetuses. Illumina HiSeq RNA sequencing was performed on Lexogen Quantseq 3' libraries derived from CV biopsies (n=11 females, n=12 males). Differential expression (DE) was performed to identify sex-linked transcriptional signatures, followed by chromosome mapping, pathway analysis, predicted protein interaction, and post-hoc linear regressions to identify transcripts that trend over time. We observe 322 transcripts DE between male and female CV from 11 to 16weeks, with 22 transcripts logFC >1. Contrary to our predictions, the difference between male and female expression of DE autosomal genes was more pronounced at the earlier gestational ages. In females, we found selective upregulation of extracellular matrix components, along with a number of X-linked genes. In males, DE transcripts centered on chromosome 19, with mitochondrial, immune, and pregnancy maintenance-related transcripts upregulated. Among the highest differentially expressed autosomal genes were CCRL2, LGALS13, and LGALS14, which are known to regulate immune cell interactions. Our results provide insight into sex-linked gene expression in late first and early second trimester developing human placentaand lay the groundwork to understand the mechanistic origins of sex differencesin prenataldevelopment.

    View details for DOI 10.1007/s43032-020-00355-8

    View details for PubMedID 33150487

  • An evolutionarily acquired microRNA shapes development of mammalian cortical projections. Proceedings of the National Academy of Sciences of the United States of America Diaz, J. L., Siththanandan, V. B., Lu, V., Gonzalez-Nava, N., Pasquina, L., MacDonald, J. L., Woodworth, M. B., Ozkan, A., Nair, R., He, Z., Sahni, V., Sarnow, P., Palmer, T. D., Macklis, J. D., Tharin, S. 2020

    Abstract

    The corticospinal tract is unique to mammals and the corpus callosum is unique to placental mammals (eutherians). The emergence of these structures is thought to underpin the evolutionary acquisition of complex motor and cognitive skills. Corticospinal motor neurons (CSMN) and callosal projection neurons (CPN) are the archetypal projection neurons of the corticospinal tract and corpus callosum, respectively. Although a number of conserved transcriptional regulators of CSMN and CPN development have been identified in vertebrates, none are unique to mammals and most are coexpressed across multiple projection neuron subtypes. Here, we discover 17 CSMN-enriched microRNAs (miRNAs), 15 of which map to a single genomic cluster that is exclusive to eutherians. One of these, miR-409-3p, promotes CSMN subtype identity in part via repression of LMO4, a key transcriptional regulator of CPN development. In vivo, miR-409-3p is sufficient to convert deep-layer CPN into CSMN. This is a demonstration of an evolutionarily acquired miRNA in eutherians that refines cortical projection neuron subtype development. Our findings implicate miRNAs in the eutherians' increase in neuronal subtype and projection diversity, the anatomic underpinnings of their complex behavior.

    View details for DOI 10.1073/pnas.2006700117

    View details for PubMedID 33139574

  • Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy Syndrome. eLife Panagiotakos, G., Haveles, C., Arjun, A., Petrova, R., Rana, A., Portmann, T., Pasca, S. P., Palmer, T. D., Dolmetsch, R. E. 2019; 8

    Abstract

    The syndromic autism spectrum disorder (ASD) Timothy Syndrome (TS) is caused by a point mutation in the alternatively spliced exon 8A of the calcium channel Cav1.2. Using mouse brain and human induced pluripotent stem cells (iPSCs), we provide evidence that the TS mutation prevents a normal developmental switch in Cav1.2 exon utilization, resulting in persistent expression of gain-of-function mutant channels during neuronal differentiation. In iPSC models, the TS mutation reduces the abundance of SATB2-expressing cortical projection neurons, leading to excess CTIP2+ neurons. We show that expression of TS-Cav1.2 channels in the embryonic mouse cortex recapitulates these differentiation defects in a calcium-dependent manner and that in utero Cav1.2 gain-and-loss of function reciprocally regulates the abundance of these neuronal populations. Our findings support the idea that disruption of developmentally-regulated calcium channel splicing patterns instructively alters differentiation in the developing cortex, providing important in vivo insights into the pathophysiology of a syndromic ASD.

    View details for DOI 10.7554/eLife.51037

    View details for PubMedID 31868578

  • "Females are not just 'protected' males:" Sex-specific vulnerabilities in placenta and brain after prenatal immune disruption. eNeuro Braun, A. E., Carpentier, P. A., Babineau, B. A., Narayan, A. R., Kielhold, M. L., Moon, H. M., Shankar, A., Su, J., Saravanapandian, V., Haditsch, U., Palmer, T. D. 2019

    Abstract

    Introduction: Current perceptions of genetic and environmental vulnerabilities in the developing fetus are biased towards male outcomes. An argument is made that males are more vulnerable to gestational complications and neurodevelopmental disorders, the implication being that an understanding of disrupted development in males is sufficient to understand causal mechanisms that are assumed to be similar but attenuated in females. Here we examine this assumption in the context of immune-driven alterations in fetal brain development and related outcomes in female and male mice. Method: Pregnant C57Bl/6 mice were treated with low dose lipopolysaccharide (LPS) at embryonic day 12.5. Placental pathology, acute fetal brain inflammation and hypoxia, long-term changes in adult cortex cytoarchitecture, altered densities and ratio of excitatory (Satb2+) to inhibitory (Parvalbumin+) neuronal subtypes, postnatal growth and behavior outcomes were compared between male and female offspring. Results: We find that while males experience more pronounced placental pathology, fetal brain hypoxia, depleted PV and Satb2+ densities, and social and learning-related behavioral abnormalities, females exhibit unique acute inflammatory signaling in fetal brain, postnatal growth delay, opposite alterations in cortical PV densities, changes in juvenile behavior, delayed postnatal body growth, and elevated anxiety-related behavior as adults. Conclusions: While males are more severely impacted by prenatal immune disruption by several measures, females exposed to the same insult exhibit a unique set of vulnerabilities and developmental consequences not present in males. Our results clearly outline disparate sex-specific features of prenatal vulnerability to inflammatory insults and warn against the casual extrapolation of male disease mechanisms to females.SIGNIFICANCE STATEMENT Given the common practice of excluding female animals from studies of maternal immune activation during pregnancy, it appears to be widely assumed that female outcomes are simply attenuated versions of more severe male outcomes. However, when females fetuses and offspring are closely examined in a model of lipopolysaccharide-induced maternal inflammation during pregnancy, we find that sex confers selective vulnerabilities and outcomes that impact the placenta, fetal brain, adult brain, and behavior in ways that are categorically distinct and in some cases opposite between females and males. Therefore, the effect of maternal immune activation on female offspring cannot be inferred from male outcomes and must be studied independently to fully understand the mechanisms that underlie prenatal vulnerability to maternal insults.

    View details for DOI 10.1523/ENEURO.0358-19.2019

    View details for PubMedID 31611335

  • COMPARATIVE FUNCTIONAL GENOMICS ANALYSES OF THE 16P11.2 DELETION AND DUPLICATION CNVS IN A HUMAN IPSC-TO-INDUCED NEURON MODEL Zhang, X., Thomas, W., Leung, L., Zhou, B., Muench, K., Plastini, M., Pattni, R., Ho, S., Ho, M., Huang, Y., Hallmayer, J., Mourrain, P., Palmer, T., Urban, A. ELSEVIER. 2019: S66
  • Adult-generated neurons born during chronic social stress are uniquely adapted to respond to subsequent chronic social stress MOLECULAR PSYCHIATRY De Miguel, Z., Haditsch, U., Palmer, T. D., Azpiroz, A., Sapolsky, R. M. 2019; 24 (8): 1178–88
  • IN-DEPTH CHARACTERIZATION OF GESTATIONAL IMMUNE DYNAMICS USING MASS CYTOMETRY Moore, A., Vivanco-Gonzalez, N., Plummer, K., Mitchel, O., Kaur, H., Rivera, M., Bendall, S., Palmer, T. W B SAUNDERS CO LTD. 2019: E87–E88
  • Human 3D cellular model of hypoxic brain injury of prematurity NATURE MEDICINE Pasca, A. M., Park, J., Shin, H., Qi, Q., Revah, O., Krasnoff, R., O'Hara, R., Willsey, A., Palmer, T. D., Pascz, S. P. 2019; 25 (5): 784-+
  • An Immune Atlas of Mid to Late Mouse Gestation. Moore, A. R., Vivanco-Gonzalez, N., Plummer, K., Kaur, H., Mitchel, O., Rivera, M., Bendall, S. C., Palmer, T. D. SAGE PUBLICATIONS INC. 2019: 345A–346A
  • Human 3D cellular model of hypoxic brain injury of prematurity. Nature medicine Pașca, A. M., Park, J. Y., Shin, H. W., Qi, Q. n., Revah, O. n., Krasnoff, R. n., O'Hara, R. n., Willsey, A. J., Palmer, T. D., Pașca, S. P. 2019

    Abstract

    Owing to recent medical and technological advances in neonatal care, infants born extremely premature have increased survival rates1,2. After birth, these infants are at high risk of hypoxic episodes because of lung immaturity, hypotension and lack of cerebral-flow regulation, and can develop a severe condition called encephalopathy of prematurity3. Over 80% of infants born before post-conception week 25 have moderate-to-severe long-term neurodevelopmental impairments4. The susceptible cell types in the cerebral cortex and the molecular mechanisms underlying associated gray-matter defects in premature infants remain unknown. Here we used human three-dimensional brain-region-specific organoids to study the effect of oxygen deprivation on corticogenesis. We identified specific defects in intermediate progenitors, a cortical cell type associated with the expansion of the human cerebral cortex, and showed that these are related to the unfolded protein response and changes. Moreover, we verified these findings in human primary cortical tissue and demonstrated that a small-molecule modulator of the unfolded protein response pathway can prevent the reduction in intermediate progenitors following hypoxia. We anticipate that this human cellular platform will be valuable for studying the environmental and genetic factors underlying injury in the developing human brain.

    View details for PubMedID 31061540

  • Characterization of Brain Dysfunction Induced by Bacterial Lipopeptides That Alter Neuronal Activity and Network in Rodent Brains JOURNAL OF NEUROSCIENCE Kim, K., Zamaleeva, A. I., Lee, Y., Ahmed, M., Kim, E., Lee, H., Pothineni, V., Tao, J., Rhee, S., Jayakumar, M., Inayathullah, M., Sivanesan, S., Red-Horse, K., Palmer, T. D., Park, J., Madison, D. V., Lee, H., Rajadas, J. 2018; 38 (50): 10672–91
  • Characterization of brain dysfunction induced by bacterial lipopeptides that alter neuronal activity and network in rodent brains. The Journal of neuroscience : the official journal of the Society for Neuroscience Kim, K., Zamaleeva, A. I., Woo Lee, Y., Ahmed, M. R., Kim, E., Lee, H., Raveendra Pothineni, V., Tao, J., Rhee, S., Jayakumar, M., Inayathullah, M., Sivanesan, S., Red-Horse, K., Palmer, T. D., Park, J., Madison, D. V., Lee, H., Rajadas, J. 2018

    Abstract

    The immunopathological states of the brain induced by bacterial lipoproteins have been well-characterized by employing biochemical and histological assays. However, these studies have limitations in determining functional states of damaged brains involving aberrant synaptic activity and network, which makes it difficult to diagnose brain disorders during bacterial infection. To address this, we investigated the effect of Pam3CSK4 (PAM), a synthetic bacterial lipopeptide, on synaptic dysfunction of female mice brains and cultured neurons in parallel. Our functional brain imaging using PET with [18F]-FDG and [18F]-FMZ revealed the brain dysfunction induced by PAM is closely aligned to disruption of neurotransmitter-related neuronal activity and functional correlation in the region of the limbic system rather than to decrease of metabolic activity of neurons in the injection area. This finding was verified by in vivo tissue experiments that analyzed synaptic and dendritic alterations in the regions where PET imaging showed abnormal neuronal activity and network. Recording of synaptic activity also revealed that PAM reorganized synaptic distribution and decreased synaptic plasticity in hippocampus. Further study using in vitro neuron cultures demonstrated that PAM decreased the number of presynapses and the frequency of mEPSC, which suggests PAM disrupts neuronal function by damaging presynapses exclusively. We also showed PAM caused aggregation of synapses around dendrites, which may have caused no significant change in expression level of synaptic proteins while synaptic number and function was impaired by PAM. New findings of this study could provide a useful guide for diagnosis and treatment of brain disorders specific to bacterial infection.SIGNIFICANCE STATEMENTIt is challenging to diagnose brain disorders caused by bacterial infection because neural damage induced by bacterial products involves non-specific neurological symptoms, which is rarely detected by laboratory tests with low spatiotemporal resolution. To better understand brain pathology, it is essential to detect functional abnormalities of brain over time. To this end, we investigated characteristic patterns of altered neuronal integrity and functional correlation between various regions in mice brains injected with bacterial lipopeptides by using PET with a goal to apply new findings to diagnosis of brain disorder specific to bacterial infection. In addition, we analyzed altered synaptic density and function using both in vivo and in vitro experimental models to understand how bacterial lipopeptides impair brain function and network.

    View details for PubMedID 30381406

  • microRNAs Refine Cortical Projection Neuron Subtype during Mammalian Development Siththanandan, V., Diaz, J., Lu, V., Gonzalez-Nava, N., Pasquina, L., MacDonald, J., Woodworth, M., Sahni, V., Sarnow, P., Palmer, T., Macklis, J., Tharin, S. WILEY. 2018: S276–S277
  • Adult-generated neurons born during chronic social stress are uniquely adapted to respond to subsequent chronic social stress. Molecular psychiatry De Miguel, Z., Haditsch, U., Palmer, T. D., Azpiroz, A., Sapolsky, R. M. 2018

    Abstract

    Chronic stress is a recognized risk factor for psychiatric and psychological disorders and a potent modulator of adult neurogenesis. Numerous studies have shown that during stress, neurogenesis decreases; however, during the recovery from the stress, neurogenesis increases. Despite the increased number of neurons born after stress, it is unknown if the function and morphology of those neurons are altered. Here we asked whether neurons in adult mice, born during the final 5 days of chronic social stress and matured during recovery from chronic social stress, are similar to neurons born with no stress conditions from a quantitative, functional and morphological perspective, and whether those neurons are uniquely adapted to respond to a subsequent stressful challenge. We observed an increased number of newborn neurons incorporated in the dentate gyrus of the hippocampus during the 10-week post-stress recovery phase. Interestingly, those new neurons were more responsive to subsequent chronic stress, as they showed more of a stress-induced decrease in spine density and branching nodes than in neurons born during a non-stress period. Our results replicate findings that the neuronal survival and incorporation of neurons in the adult dentate gyrus increases after chronic stress and suggest that such neurons are uniquely adapted in the response to future social stressors. This finding provides a potential mechanism for some of the long-term hippocampal effects of stress.

    View details for PubMedID 29311652

  • RNA-protein interaction detection in living cells. Nature methods Ramanathan, M. n., Majzoub, K. n., Rao, D. S., Neela, P. H., Zarnegar, B. J., Mondal, S. n., Roth, J. G., Gai, H. n., Kovalski, J. R., Siprashvili, Z. n., Palmer, T. D., Carette, J. E., Khavari, P. A. 2018

    Abstract

    RNA-protein interactions play numerous roles in cellular function and disease. Here we describe RNA-protein interaction detection (RaPID), which uses proximity-dependent protein labeling, based on the BirA* biotin ligase, to rapidly identify the proteins that bind RNA sequences of interest in living cells. RaPID displays utility in multiple applications, including in evaluating protein binding to mutant RNA motifs in human genetic disorders, in uncovering potential post-transcriptional networks in breast cancer, and in discovering essential host proteins that interact with Zika virus RNA. To improve the BirA*-labeling component of RaPID, moreover, a new mutant BirA* was engineered from Bacillus subtilis, termed BASU, that enables >1,000-fold faster kinetics and >30-fold increased signal-to-noise ratio over the prior standard Escherichia coli BirA*, thereby enabling direct study of RNA-protein interactions in living cells on a timescale as short as 1 min.

    View details for PubMedID 29400715

  • A Knockin Reporter Allows Purification and Characterization of mDA Neurons from Heterogeneous Populations CELL REPORTS Xia, N., Fang, F., Zhang, P., Cui, J., Tep-Cullison, C., Hamerley, T., Lee, H. J., Palmer, T., Bothner, B., Lee, J. H., Pera, R. R. 2017; 18 (10): 2533-2546

    Abstract

    Generation of midbrain dopaminergic (mDA) neurons from human pluripotent stem cells provides a platform for inquiry into basic and translational studies of Parkinson's disease (PD). However, heterogeneity in differentiation in vitro makes it difficult to identify mDA neurons in culture or in vivo following transplantation. Here, we report the generation of a human embryonic stem cell (hESC) line with a tyrosine hydroxylase (TH)-RFP (red fluorescent protein) reporter. We validated that RFP faithfully mimicked TH expression during differentiation. Use of this TH-RFP reporter cell line enabled purification of mDA-like neurons from heterogeneous cultures with subsequent characterization of neuron transcriptional and epigenetic programs (global binding profiles of H3K27ac, H3K4me1, and 5-hydroxymethylcytosine [5hmC]) at four different stages of development. We anticipate that the tools and data described here will contribute to the development of mDA neurons for applications in disease modeling and/or drug screening and cell replacement therapies for PD.

    View details for DOI 10.1016/j.celrep.2017.02.023

    View details for PubMedID 28273465

  • Phosphorylation of aB-crystallin supports reactive astrogliosis in demyelination. Proceedings of the National Academy of Sciences of the United States of America Kuipers, H. F., Yoon, J., van Horssen, J., Han, M. H., Bollyky, P. L., Palmer, T. D., Steinman, L. 2017; 114 (9): E1745-E1754

    Abstract

    The small heat shock protein αB-crystallin (CRYAB) has been implicated in multiple sclerosis (MS) pathogenesis. Earlier studies have indicated that CRYAB inhibits inflammation and attenuates clinical disease when administered in the experimental autoimmune encephalomyelitis model of MS. In this study, we evaluated the role of CRYAB in primary demyelinating events. Using the cuprizone model of demyelination, a noninflammatory model that allows the analysis of glial responses in MS, we show that endogenous CRYAB expression is associated with increased severity of demyelination. Moreover, we demonstrate a strong correlation between the expression of CRYAB and the extent of reactive astrogliosis in demyelinating areas and in in vitro assays. In addition, we reveal that CRYAB is differentially phosphorylated in astrocytes in active demyelinating MS lesions, as well as in cuprizone-induced lesions, and that this phosphorylation is required for the reactive astrocyte response associated with demyelination. Furthermore, taking a proteomics approach to identify proteins that are bound by the phosphorylated forms of CRYAB in primary cultured astrocytes, we show that there is clear differential binding of protein targets due to the specific phosphorylation of CRYAB. Subsequent Ingenuity Pathway Analysis of these targets reveals implications for intracellular pathways and biological processes that could be affected by these modifications. Together, these findings demonstrate that astrocytes play a pivotal role in demyelination, making them a potential target for therapeutic intervention, and that phosphorylation of CRYAB is a key factor supporting the pathogenic response of astrocytes to oligodendrocyte injury.

    View details for DOI 10.1073/pnas.1621314114

    View details for PubMedID 28196893

    View details for PubMedCentralID PMC5338510

  • Functional Impairment in Miro Degradation and Mitophagy Is a Shared Feature in Familial and Sporadic Parkinson's Disease CELL STEM CELL Hsieh, C., Shaltouki, A., Gonzalez, A. E., Da Cruz, A. B., Burbulla, L. F., St Lawrence, E., Schule, B., Krainc, D., Palmer, T. D., Wang, X. 2016; 19 (6): 709-724

    Abstract

    Mitochondrial movements are tightly controlled to maintain energy homeostasis and prevent oxidative stress. Miro is an outer mitochondrial membrane protein that anchors mitochondria to microtubule motors and is removed to stop mitochondrial motility as an early step in the clearance of dysfunctional mitochondria. Here, using human induced pluripotent stem cell (iPSC)-derived neurons and other complementary models, we build on a previous connection of Parkinson's disease (PD)-linked PINK1 and Parkin to Miro by showing that a third PD-related protein, LRRK2, promotes Miro removal by forming a complex with Miro. Pathogenic LRRK2G2019S disrupts this function, delaying the arrest of damaged mitochondria and consequently slowing the initiation of mitophagy. Remarkably, partial reduction of Miro levels in LRRK2G2019S human neuron and Drosophila PD models rescues neurodegeneration. Miro degradation and mitochondrial motility are also impaired in sporadic PD patients. We reveal that prolonged retention of Miro, and the downstream consequences that ensue, may constitute a central component of PD pathogenesis.

    View details for DOI 10.1016/j.stem.2016.08.002

    View details for Web of Science ID 000389474900010

    View details for PubMedCentralID PMC5135570

  • Functional Impairment in Miro Degradation and Mitophagy Is a Shared Feature in Familial and Sporadic Parkinson's Disease. Cell stem cell Hsieh, C., Shaltouki, A., Gonzalez, A. E., Bettencourt Da Cruz, A., Burbulla, L. F., St Lawrence, E., Schüle, B., Krainc, D., Palmer, T. D., Wang, X. 2016

    Abstract

    Mitochondrial movements are tightly controlled to maintain energy homeostasis and prevent oxidative stress. Miro is an outer mitochondrial membrane protein that anchors mitochondria to microtubule motors and is removed to stop mitochondrial motility as an early step in the clearance of dysfunctional mitochondria. Here, using human induced pluripotent stem cell (iPSC)-derived neurons and other complementary models, we build on a previous connection of Parkinson's disease (PD)-linked PINK1 and Parkin to Miro by showing that a third PD-related protein, LRRK2, promotes Miro removal by forming a complex with Miro. Pathogenic LRRK2G2019S disrupts this function, delaying the arrest of damaged mitochondria and consequently slowing the initiation of mitophagy. Remarkably, partial reduction of Miro levels in LRRK2G2019S human neuron and Drosophila PD models rescues neurodegeneration. Miro degradation and mitochondrial motility are also impaired in sporadic PD patients. We reveal that prolonged retention of Miro, and the downstream consequences that ensue, may constitute a central component of PD pathogenesis.

    View details for DOI 10.1016/j.stem.2016.08.002

    View details for PubMedID 27618216

    View details for PubMedCentralID PMC5135570

  • The Role of the Microenvironmental Niche in Declining Stem-Cell Functions Associated with Biological Aging COLD SPRING HARBOR PERSPECTIVES IN MEDICINE DeCarolis, N. A., Kirby, E. D., Wyss-Coray, T., Palmer, T. D. 2015; 5 (12)

    Abstract

    Aging is strongly correlated with decreases in neurogenesis, the process by which neural stem and progenitor cells proliferate and differentiate into new neurons. In addition to stem-cell-intrinsic factors that change within the aging stem-cell pool, recent evidence emphasizes new roles for systemic and microenvironmental factors in modulating the neurogenic niche. This article focuses on new insights gained through the use of heterochronic parabiosis models, in which an old mouse and a young circulatory system are joined. By studying the brains of both young and old mice, researchers are beginning to uncover circulating proneurogenic "youthful" factors and "aging" factors that decrease stem-cell activity and neurogenesis. Ultimately, the identification of factors that influence stem-cell aging may lead to strategies that slow or even reverse age-related decreases in neural-stem-cell (NSC) function and neurogenesis.

    View details for DOI 10.1101/cshperspect.a025874

    View details for Web of Science ID 000368599500002

  • Aging-Like Changes in the Transcriptome of Irradiated Microglia GLIA Li, M. D., Burns, T. C., Kumar, S., Morgan, A. A., Sloan, S. A., Palmer, T. D. 2015; 63 (5): 754-767

    Abstract

    Whole brain irradiation remains important in the management of brain tumors. Although necessary for improving survival outcomes, cranial irradiation also results in cognitive decline in long-term survivors. A chronic inflammatory state characterized by microglial activation has been implicated in radiation-induced brain injury. We here provide the first comprehensive transcriptional profile of irradiated microglia. Fluorescence-activated cell sorting was used to isolate CD11b+ microglia from the hippocampi of C57BL/6 and Balb/c mice 1 month after 10 Gy cranial irradiation. Affymetrix gene expression profiles were evaluated using linear modeling and rank product analyses. One month after irradiation, a conserved irradiation signature across strains was identified, comprising 448 and 85 differentially up- and downregulated genes, respectively. Gene set enrichment analysis demonstrated enrichment for inflammation, including M1 macrophage-associated genes, but also an unexpected enrichment for extracellular matrix and blood coagulation-related gene sets, in contrast previously described microglial states. Weighted gene coexpression network analysis confirmed these findings and further revealed alterations in mitochondrial function. The RNA-seq transcriptome of microglia 24-h postradiation proved similar to the 1-month transcriptome, but additionally featured alterations in apoptotic and lysosomal gene expression. Reanalysis of published aging mouse microglia transcriptome data demonstrated striking similarity to the 1-month irradiated microglia transcriptome, suggesting that shared mechanisms may underlie aging and chronic irradiation-induced cognitive decline. GLIA 2015;63:754-767.

    View details for DOI 10.1002/glia.22782

    View details for Web of Science ID 000351622600003

    View details for PubMedID 25690519

    View details for PubMedCentralID PMC4625786

  • Acute Subclinical Maternal Inflammation in Late Pregnancy Ozen, M., Zhao, H., Winn, V. D., Lewis, D. B., Kalish, F., Palmer, T. D., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2015: 89A–90A
  • The Role of the Microenvironmental Niche in Declining Stem-Cell Functions Associated with Biological Aging. Cold Spring Harbor perspectives in medicine DeCarolis, N. A., Kirby, E. D., Wyss-Coray, T., Palmer, T. D. 2015; 5 (12)

    Abstract

    Aging is strongly correlated with decreases in neurogenesis, the process by which neural stem and progenitor cells proliferate and differentiate into new neurons. In addition to stem-cell-intrinsic factors that change within the aging stem-cell pool, recent evidence emphasizes new roles for systemic and microenvironmental factors in modulating the neurogenic niche. This article focuses on new insights gained through the use of heterochronic parabiosis models, in which an old mouse and a young circulatory system are joined. By studying the brains of both young and old mice, researchers are beginning to uncover circulating proneurogenic "youthful" factors and "aging" factors that decrease stem-cell activity and neurogenesis. Ultimately, the identification of factors that influence stem-cell aging may lead to strategies that slow or even reverse age-related decreases in neural-stem-cell (NSC) function and neurogenesis.

    View details for DOI 10.1101/cshperspect.a025874

    View details for PubMedID 26627453

  • The Relationship Between Serial [(18) F]PBR06 PET Imaging of Microglial Activation and Motor Function Following Stroke in Mice MOLECULAR IMAGING AND BIOLOGY Lartey, F. M., Ahn, G., Ali, R., Rosenblum, S., Miao, Z., Arksey, N., Shen, B., Colomer, M. V., Rafat, M., Liu, H., Alejandre-Alcazar, M. A., Chen, J. W., Palmer, T., Chin, F. T., Guzman, R., Loo, B. W., Graves, E. 2014; 16 (6): 821-829

    Abstract

    Using [(18) F]PBR06 positron emission tomography (PET) to characterize the time course of stroke-associated neuroinflammation (SAN) in mice, to evaluate whether brain microglia influences motor function after stroke, and to demonstrate the use of [(18) F]PBR06 PET as a therapeutic assessment tool.Stroke was induced by transient middle cerebral artery occlusion (MCAO) in Balb/c mice (control, stroke, and stroke with poststroke minocycline treatment). [18 F]PBR06 PET/CT imaging, rotarod tests, and immunohistochemistry (IHC) were performed 3, 11, and 22 days poststroke induction (PSI).The stroke group exhibited significantly increased microglial activation, and impaired motor function. Peak microglial activation was 11 days PSI. There was a strong association between microglial activation, motor function, and microglial protein expression on IHC. Minocycline significantly reduced microglial activation and improved motor function by day 22 PSI.[18 F]PBR06 PET imaging noninvasively characterizes the time course of SAN, and shows increased microglial activation is associated with decreased motor function.

    View details for DOI 10.1007/s11307-014-0745-0

    View details for Web of Science ID 000345281600009

  • The relationship between serial [(18)?F]PBR06 PET imaging of microglial activation and motor function following stroke in mice. Molecular imaging and biology Lartey, F. M., Ahn, G., Ali, R., Rosenblum, S., Miao, Z., Arksey, N., Shen, B., Colomer, M. V., Rafat, M., Liu, H., Alejandre-Alcazar, M. A., Chen, J. W., Palmer, T., Chin, F. T., Guzman, R., Loo, B. W., Graves, E. 2014; 16 (6): 821-829

    Abstract

    Using [(18) F]PBR06 positron emission tomography (PET) to characterize the time course of stroke-associated neuroinflammation (SAN) in mice, to evaluate whether brain microglia influences motor function after stroke, and to demonstrate the use of [(18) F]PBR06 PET as a therapeutic assessment tool.Stroke was induced by transient middle cerebral artery occlusion (MCAO) in Balb/c mice (control, stroke, and stroke with poststroke minocycline treatment). [18 F]PBR06 PET/CT imaging, rotarod tests, and immunohistochemistry (IHC) were performed 3, 11, and 22 days poststroke induction (PSI).The stroke group exhibited significantly increased microglial activation, and impaired motor function. Peak microglial activation was 11 days PSI. There was a strong association between microglial activation, motor function, and microglial protein expression on IHC. Minocycline significantly reduced microglial activation and improved motor function by day 22 PSI.[18 F]PBR06 PET imaging noninvasively characterizes the time course of SAN, and shows increased microglial activation is associated with decreased motor function.

    View details for DOI 10.1007/s11307-014-0745-0

    View details for PubMedID 24865401

  • Stress and glucocorticoids promote oligodendrogenesis in the adult hippocampus MOLECULAR PSYCHIATRY Chetty, S., Friedman, A. R., Taravosh-Lahn, K., Kirby, E. D., Mirescu, C., Guo, F., Krupik, D., Nicholas, A., Geraghty, C., Krishnamurthy, A., Tsai, M., Covarrubias, D., Wong, A. T., Francis, D. D., Sapolsky, R. M., Palmer, T. D., PLEASURE, D., Kaufer, D. 2014; 19 (12): 1275-1283

    Abstract

    Stress can exert long-lasting changes on the brain that contribute to vulnerability to mental illness, yet mechanisms underlying this long-term vulnerability are not well understood. We hypothesized that stress may alter the production of oligodendrocytes in the adult brain, providing a cellular and structural basis for stress-related disorders. We found that immobilization stress decreased neurogenesis and increased oligodendrogenesis in the dentate gyrus (DG) of the adult rat hippocampus and that injections of the rat glucocorticoid stress hormone corticosterone (cort) were sufficient to replicate this effect. The DG contains a unique population of multipotent neural stem cells (NSCs) that give rise to adult newborn neurons, but oligodendrogenic potential has not been demonstrated in vivo. We used a nestin-CreER/YFP transgenic mouse line for lineage tracing and found that cort induces oligodendrogenesis from nestin-expressing NSCs in vivo. Using hippocampal NSCs cultured in vitro, we further showed that exposure to cort induced a pro-oligodendrogenic transcriptional program and resulted in an increase in oligodendrogenesis and decrease in neurogenesis, which was prevented by genetic blockade of glucocorticoid receptor (GR). Together, these results suggest a novel model in which stress may alter hippocampal function by promoting oligodendrogenesis, thereby altering the cellular composition and white matter structure.

    View details for DOI 10.1038/mp.2013.190

    View details for PubMedID 24514565

  • Differential phosphorylation of alpha B-crystallin in astrocytes and oligodendrocytes suggests a diversity in its biological function Kuipers, H. F., Yoon, J., Winderl, J., Van Horssen, J., Han, M. H., Palmer, T. D., Steinman, L. ELSEVIER SCIENCE BV. 2014: 157–58
  • PET Imaging of Stroke-Induced Neuroinflammation in Mice Using [F-18]PBR06 MOLECULAR IMAGING AND BIOLOGY Lartey, F. M., Ahn, G., Shen, B., Cord, K., Smith, T., Chua, J. Y., Rosenblum, S., Liu, H., James, M. L., Chernikova, S., Lee, S. W., Pisani, L. J., Tirouvanziam, R., Chen, J. W., Palmer, T. D., Chin, F. T., Guzman, R., Graves, E. E., Loo, B. W. 2014; 16 (1): 109-117

    Abstract

    The purpose of this study is to evaluate the 18 kDa translocator protein (TSPO) radioligand [(18)F]N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline ([(18)F]PBR06) as a positron emission tomography (PET) imaging biomarker of stroke-induced neuroinflammation in a rodent model.Stroke was induced by transient middle cerebral artery occlusion in Balb/c mice. Dynamic PET/CT imaging with displacement and preblocking using PK111195 was performed 3 days later. PET data were correlated with immunohistochemistry (IHC) for the activated microglial markers TSPO and CD68 and with autoradiography.[(18)F]PBR06 accumulation peaked within the first 5 min postinjection, then decreased gradually, remaining significantly higher in infarct compared to noninfarct regions. Displacement or preblocking with PK11195 eliminated the difference in [(18)F]PBR06 uptake between infarct and noninfarct regions. Autoradiography and IHC correlated well spatially with uptake on PET.[(18)F]PBR06 PET specifically images TSPO in microglial neuroinflammation in a mouse model of stroke and shows promise for imaging and monitoring microglial activation/neuroinflammation in other disease models.

    View details for DOI 10.1007/s11307-013-0664-5

    View details for PubMedID 23836504

  • Stereotypical alterations in cortical patterning are associated with maternal illness-induced placental dysfunction. journal of neuroscience Carpentier, P. A., Haditsch, U., Braun, A. E., Cantu, A. V., Moon, H. M., Price, R. O., Anderson, M. P., Saravanapandian, V., Ismail, K., Rivera, M., Weimann, J. M., Palmer, T. D. 2013; 33 (43): 16874-16888

    Abstract

    We have previously shown in mice that cytokine-mediated damage to the placenta can temporarily limit the flow of nutrients and oxygen to the fetus. The placental vulnerability is pronounced before embryonic day 11, when even mild immune challenge results in fetal loss. As gestation progresses, the placenta becomes increasingly resilient to maternal inflammation, but there is a narrow window in gestation when the placenta is still vulnerable to immune challenge yet resistant enough to allow for fetal survival. This gestational window correlates with early cortical neurogenesis in the fetal brain. Here, we show that maternal illness during this period selectively alters the abundance and laminar positioning of neuronal subtypes influenced by the Tbr1, Satb2, and Ctip2/Fezf2 patterning axis. The disturbances also lead to a laminar imbalance in the proportions of projection neurons and interneurons in the adult and are sufficient to cause changes in social behavior and cognition. These data illustrate how the timing of an illness-related placental vulnerability causes developmental alterations in neuroanatomical systems and behaviors that are relevant to autism spectrum disorders.

    View details for DOI 10.1523/JNEUROSCI.4654-12.2013

    View details for PubMedID 24155294

    View details for PubMedCentralID PMC3807021

  • Natural Killer Cell-Activating Receptor NKG2D Mediates Innate Immune Targeting of Allogeneic Neural Progenitor Cell Grafts STEM CELLS Phillips, L. K., Gould, E. A., Babu, H., Krams, S. M., Palmer, T. D., Martinez, O. M. 2013; 31 (9): 1829-1839

    Abstract

    Cell replacement therapy holds promise for a number of untreatable neurological or psychiatric diseases but the immunogenicity of cellular grafts remains controversial. Emerging stem cell and reprogramming technologies can be used to generate autologous grafts that minimize immunological concerns but autologous grafts may carry an underlying genetic vulnerability that reduces graft efficacy or survival. Healthy allogeneic grafts are an attractive and commercially scalable alternative if immunological variables can be controlled. Stem cells and immature neural progenitor cells (NPC) do not express major histocompatibility complex (MHC) antigens and can evade adaptive immune surveillance. Nevertheless, in an experimental murine model, allogeneic NPCs do not survive and differentiate as well as syngeneic grafts, even when traditional immunosuppressive treatments are used. In this study, we show that natural killer (NK) cells recognize the lack of self-MHC antigens on NPCs and pose a barrier to NPC transplantation. NK cells readily target both syngeneic and allogeneic NPC, and killing is modulated primarily by NK-inhibiting "self" class I MHC and NK-activating NKG2D-ligand expression. The absence of NKG2D signaling in NK cells significantly improves NPC-derived neuron survival and differentiation. These data illustrate the importance of innate immune mechanisms in graft outcome and the potential value of identifying and targeting NK cell-activating ligands that may be expressed by stem cell derived grafts.

    View details for DOI 10.1002/stem.1422

    View details for Web of Science ID 000325255700010

    View details for PubMedID 23733329

  • Neuronal Rac1 is required for learning-evoked neurogenesis. journal of neuroscience Haditsch, U., Anderson, M. P., Freewoman, J., Cord, B., Babu, H., Brakebusch, C., Palmer, T. D. 2013; 33 (30): 12229-12241

    Abstract

    Hippocampus-dependent learning and memory relies on synaptic plasticity as well as network adaptations provided by the addition of adult-born neurons. We have previously shown that activity-induced intracellular signaling through the Rho family small GTPase Rac1 is necessary in forebrain projection neurons for normal synaptic plasticity in vivo, and here we show that selective loss of neuronal Rac1 also impairs the learning-evoked increase in neurogenesis in the adult mouse hippocampus. Earlier work has indicated that experience elevates the abundance of adult-born neurons in the hippocampus primarily by enhancing the survival of neurons produced just before the learning event. Loss of Rac1 in mature projection neurons did reduce learning-evoked neurogenesis but, contrary to our expectations, these effects were not mediated by altering the survival of young neurons in the hippocampus. Instead, loss of neuronal Rac1 activation selectively impaired a learning-evoked increase in the proliferation and accumulation of neural precursors generated during the learning event itself. This indicates that experience-induced alterations in neurogenesis can be mechanistically resolved into two effects: (1) the well documented but Rac1-independent signaling cascade that enhances the survival of young postmitotic neurons; and (2) a previously unrecognized Rac1-dependent signaling cascade that stimulates the proliferative production and retention of new neurons generated during learning itself.

    View details for DOI 10.1523/JNEUROSCI.2939-12.2013

    View details for PubMedID 23884931

    View details for PubMedCentralID PMC3721836

  • Neuronal Rac1 Is Required for Learning-Evoked Neurogenesis JOURNAL OF NEUROSCIENCE Haditsch, U., Anderson, M. P., Freewoman, J., Cord, B., Babu, H., Brakebusch, C., Palmer, T. D. 2013; 33 (30): 12229-12241

    Abstract

    Hippocampus-dependent learning and memory relies on synaptic plasticity as well as network adaptations provided by the addition of adult-born neurons. We have previously shown that activity-induced intracellular signaling through the Rho family small GTPase Rac1 is necessary in forebrain projection neurons for normal synaptic plasticity in vivo, and here we show that selective loss of neuronal Rac1 also impairs the learning-evoked increase in neurogenesis in the adult mouse hippocampus. Earlier work has indicated that experience elevates the abundance of adult-born neurons in the hippocampus primarily by enhancing the survival of neurons produced just before the learning event. Loss of Rac1 in mature projection neurons did reduce learning-evoked neurogenesis but, contrary to our expectations, these effects were not mediated by altering the survival of young neurons in the hippocampus. Instead, loss of neuronal Rac1 activation selectively impaired a learning-evoked increase in the proliferation and accumulation of neural precursors generated during the learning event itself. This indicates that experience-induced alterations in neurogenesis can be mechanistically resolved into two effects: (1) the well documented but Rac1-independent signaling cascade that enhances the survival of young postmitotic neurons; and (2) a previously unrecognized Rac1-dependent signaling cascade that stimulates the proliferative production and retention of new neurons generated during learning itself.

    View details for DOI 10.1523/JNEUROSCI.2939-12.2013

    View details for Web of Science ID 000322168600010

    View details for PubMedID 23884931

    View details for PubMedCentralID PMC3721836

  • DIFFERENTIAL ROLES FOR THE SMALL HEAT SHOCK PROTEIN ALPHA B-CRYSTALLIN IN DE- & REMYELINATION 11th European Meeting on Glial Cell Function in Health and Disease Kuipers, H., Yoon, J., Winderl, J., van Horssen, J., Palmer, T., Steinman, L. WILEY-BLACKWELL. 2013: S185–S185
  • Absence of CCL2 is sufficient to restore hippocampal neurogenesis following cranial irradiation. Brain, behavior, and immunity Lee, S. W., Haditsch, U., Cord, B. J., Guzman, R., Kim, S. J., Boettcher, C., Priller, J., Ormerod, B. K., Palmer, T. D. 2013; 30: 33-44

    Abstract

    Cranial irradiation for the treatment of brain tumors causes a delayed and progressive cognitive decline that is pronounced in young patients. Dysregulation of neural stem and progenitor cells is thought to contribute to these effects by altering early childhood brain development. Earlier work has shown that irradiation creates a chronic neuroinflammatory state that severely and selectively impairs postnatal and adult neurogenesis. Here we show that irradiation induces a transient non-classical cytokine response with selective upregulation of CCL2/monocyte chemoattractant protein-1 (MCP-1). Absence of CCL2 signaling in the hours after irradiation is alone sufficient to attenuate chronic microglia activation and allow the recovery of neurogenesis in the weeks following irradiation. This identifies CCL2 signaling as a potential clinical target for moderating the long-term defects in neural stem cell function following cranial radiation in children.

    View details for DOI 10.1016/j.bbi.2012.09.010

    View details for PubMedID 23041279

  • Differential roles of TNFR1 and TNFR2 signaling in adult hippocampal neurogenesis. Brain, behavior, and immunity Chen, Z., Palmer, T. D. 2013; 30: 45-53

    Abstract

    Tumor necrosis factor alpha (TNFα) is a potent inhibitor of neurogenesis in vitro but here we show that TNFα signaling has both positive and negative effects on neurogenesis in vivo and is required to moderate the negative impact of cranial irradiation on hippocampal neurogenesis. In vitro, basal levels of TNFα signaling through TNFR2 are required for normal neural progenitor cell proliferation while basal signaling through TNFR1 impairs neural progenitor proliferation. TNFR1 also mediates further reductions in proliferation and elevated cell death following exposure to recombinant TNFα. In vivo, TNFR1(-/-) and TNFα(-/-) animals have elevated baseline neurogenesis in the hippocampus, whereas absence of TNFR2 decreases baseline neurogenesis. TNFα is also implicated in defects in neurogenesis that follow radiation injury but we find that loss of TNFR1 has no protective effects on neurogenesis and loss of TNFα or TNFR2 worsened the effects of radiation injury on neurogenesis. We conclude that the immunomodulatory signaling of TNFα mediated by TNFR2 is more significant to radiation injury outcome than the proinflammatory signaling mediated through TNFR1.

    View details for DOI 10.1016/j.bbi.2013.01.083

    View details for PubMedID 23402793

    View details for PubMedCentralID PMC3641155