Single Cell Transcriptional Approaches to Understanding the Life of Mammalian Neural Stem Cells

Adult neural stem cells (NSCs) build, maintain and are involved in repair of the mammalian brain. Adult NSCs reside within two distinct niches of the forebrain: the hippocampal dentate gyrus and the ventricular-subventricular zone (V-SVZ) along the lateral ventricles. Both adult NSC populations exhibit specific functions within their niches: hippocampal NSCs produce granule neurons of the dentate gyrus involved in spatial learning and memory and V-SVZ NSCs produce neurons required for olfactory learning and oligodendrocytes for white matter development and repair. Adult NSCs derive from embryonic neural precursors which are tasked with building the brain. Unlike their adult NSC progeny, embryonic precursors produce a wide variety of neuronal and glial cell types during development. Whether adult NSCs are fundamentally different and intrinsically less multipotential than their embryonic predecessors are largely unknown. This thesis has addressed this by characterizing and comparing the molecular profiles of adult forebrain NSCs and their embryonic predecessors to ascertain whether they are similar or different. First, I performed single cell transcriptional profiling on embryonic neural precursors and identified a novel core signature for embryonic neural precursors that is largely maintained in adult V-SVZ NSCs indicating that the two populations are fundamentally molecularly similar. Second, I have coupled single cell transcriptional profiling with lineage tracing to follow different populations of embryonic precursors as they progress into adult V-SVZ NSCs. This analysis revealed that the transition from an embryonic precursor to an adult NSC does not involve a fundamental change in cell identity but rather reflects a conversion from an active to a dormant state. Third, I compared the molecular profiles of V-SVZ NSCs with hippocampal NSCs and show that both forebrain NSC populations share the same core signature and undergo similar transitions from embryogenesis to adulthood. These findings support a model in which NSCs of either hippocampal or V-SVZ origin possess conserved molecular properties regardless of their age or respective functions. This model further suggests that the different functions exhibited by NSCs at different ages may not be a product of intrinsic programming but may instead reflect the influence of the environment they reside in.Ph.D