Cell genesis in the mammalian central nervous system

The present thesis explores three separate areas of study related to cell genesis in the central nervous system. In the first, I sought to identify and explore mechanisms responsible for region-specific growth and germinal layer formation in developing central nervous system. I report that CNTF/LIF/gp130 receptor signaling promotes the self-renewal/expansion of a subpopulation of ventricular zone (VZ) precursors. This process is necessary for normal growth of the early ventral forebrain and for maintaining a gradient of VZ precursor differentiation in the lateral ganglionic eminence, as defined by GSH2, MASH1 and DLX2 transcription factor expression. This signaling pathway had the opposite effect in the spinal cord, functioning to promote neuronal differentiation, rather than renewal/expansion of the VZ cell population.; Radial glial cells (RGCs) are specialized cells in the embryonic brain that function as VZ precursors and as a scaffold to support neuron migration. Little is known about the signals responsible for their generation and differentiation. In the second major study of the thesis, I investigated the signals responsible for the formation of radial glia from NSCs. I found that epidermal growth factor receptor signaling was sufficient to regulate both the generation and differentiation of morphologically, antigenically, and functionally defined RGCs from neural stem cells (NSCs). Although RGCs are not normally present in the adult brain, epidermal growth factor stimulated adult forebrain neural stem cells to generate functional RGCs within the adult forebrain germinal zone in vivo. These results suggest that neural stem cells can give rise to RGCs and that RGC-guided neuronal migration can be recapitulated in the adult CNS.; Finally, myelination in the adult central nervous system represents an important but poorly understood form of neural plasticity that may be sexually dimorphic. In the final major study of the thesis, the remission of multiple sclerosis during pregnancy led me to hypothesize that remyelination is enhanced in the maternal brain. Here I report increased generation of myelin-forming oligodendrocytes in the maternal murine central nervous system. Remarkably, pregnant mice have an enhanced ability to remyelinate white matter lesions. The hormone prolactin regulates oligodendrocyte precursor proliferation and mimics the regenerative effects of pregnancy. This suggests that maternal white matter plasticity imparts a striking ability to repair demyelination and identifies prolactin as a potential therapeutic agent.; The present thesis reveals new information about the NSC niche during brain development, the capacity for adult NSCs to recapitulate developmental processes, and the adaptive mechanisms controlling the generation of new oligodendrocytes in the adult CNS.