The adult mammalian brain possesses the remarkable capacity for generating new neurons throughout life. Adult mouse hippocampal neurogenesis is thought to recapitulate many hallmarks of neurodevelopment and occurs in a spatially-defined, temporally-dilated manner. Because the mature central nervous system context is often thought of as inhospitable to cell growth or genesis, it is important to understand how the complex adult neurogenesis and neurodevelopmental processes can occur, and in what ways these processes may differ from those of embryonic neurogenesis. The thesis research presented here examines how adult mouse hippocampal neurogenesis occurs at a cellular level throughout neural development from stem cell to nerve cell.The first part of my thesis examines the regulation of cell fate decisions made by neural stem cells to generate diverse cell types in the adult mouse hippocampus. Under normal conditions, neural stem cells generate cells of only the neuronal and astroglial lineages. However, conditional inactivation of an important negative regulator of Ras signaling, neurofibromin 1 (NF1), revealed an intrinsic capacity of adult hippocampal neural stem cells to generate the oligodendroglial lineage. This finding suggests a novel, non-canonical paradigm of stem cell regulation via active limitation of stem cell plasticity.The second part of my thesis examines how newborn neurons migrate within the adult mouse hippocampus. Adult-born hippocampal neurons are glutamatergic, excitatory dentate granule cells that are thought to abide by migration rules of the developing neocortex to migrate exclusively in a radial direction away from the neurogenic niche. Using a novel system to visualize clones of neurogenic neural stem cells and their clonal progeny, I quantitatively studied newborn neuron migration. I found that newborn neurons exhibit extensive and almost exclusive tangential migration, which utilizes direct contacts with niche vasculature as a migration substrate. This finding represents a novel form of glutamatergic cell migration.The third part of my thesis examines how newborn neurons grow their dendrites and axons in the adult mouse hippocampus. To date, studying axon development with single-axon resolution has been impossible due to technological limitations precluding capturing whole, intact, fine axonal processes. In collaboration with Kurt Sailor, I developed a new technology, named SEBI (serial end-block imaging), to seamlessly reconstruct large volumes of tissue and recover full, native, intact cellular structure with high resolution. Using this technology, I studied the development of newborn hippocampal granule cells and discovered complex axonal projections and ordered lamination patterns. My findings represent the first characterization of the development and structure of the full intact, primary dendrite and axon structure for newborn hippocampal granule cells.In summary, my thesis work presented here has contributed significant novel discoveries in neurodevelopment in the adult mouse hippocampus. I have found novel mechanisms for regulating neural stem cell fate decisions, a new form of excitatory neuron migration, and complex dendrite and axon development in the mature central nervous system. My findings have great relevance to better understanding brain development, degeneration, and regeneration.
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