Research in the Palmer Lab

Human brain development and maintenance is orchestrated by a complex interaction of genetic and environmental factors. Our research examines how neural stem cells respond to these cues to add and integrate new neurons into functional circuits. 

NEURAL STEM CELLS IN DEVELOPMENT: Our studies of neurogenesis in the developing brain focus on the influence of maternal health or illness on fetal brain development. In mice, even mild maternal illness during early pregnancy can alter stem cell activity in the developing fetal brain. This leads to subtle changes in social behavior and cognition reminiscent of autism. Prior epidemiological studies have noted that autoimmune events, allergies, or infections during pregnancy may increase the risk of autism in the child. Our ongoing research focuses on genetic risk factors for autism that may exacerbate the effects of maternal illness on fetal brain development. 

NEURAL STEM CELLS IN THE ADULT: Our studies of stem cells in the adult focus on the hippocampus, one of the few areas where neurogenesis naturally continues throughout life. We have found that this region contains a unique arrangement of cells and signals that instruct stem cells to generate new neurons. Our goal is to determine if manipulating these signals might augment neurogenesis and enhance stem cell mediated CNS repair. 

STEM CELLS TO STUDY CNS INJURY AND DISEASE: Using information gained from studying neural stem cells in development and in the adult, we have been able to reconstruct the conditions of neurogenesis in the Petri dish. We are now able to use human embryonic stem cells and non-embryonic induced pluripotent stem cells to generate several types of human neurons, including those lost in Parkinson’s disease. 

Pluripotent stem cells from patients who suffer from neurological disorders promise to be fundamentally important tools for identifying disease mechanisms or for providing neurons for repair. Understanding how new neurons are produced, and more importantly integrated, is critical for guiding efforts to restore function. With sufficient insights into the native control of neurogenesis, it may be possible to ameliorate the devastating effects of neurodevelopmental disease, injury, or aging-related disorders such as Parkinson’s or Alzheimer’s disease.

Professor of Neurosurgery, Emeritus

Publications

  • 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