Investigating the Mechanisms of Perinatal Neuron Degeneration, Survival, and their Differentiation from Neural Precursor Cells of the V-SVZ

For the formation and maintenance of functional neuronal networks, the generation of neurons from their progenitors developmentally as well as their continued survival once the circuitry has been established are both crucial for nervous system homeostasis and plasticity, with disruptions resulting in neuropathologies. For the integrity of this process, first, cellular mechanisms need to temporally orchestrate the correct neuronal fate delineation from multipotent precursors and second, transduced pro-life signals need to suppress degeneration-promoting transcriptional programs to ensure continued survival. In this thesis, I describe a novel 4E-T-based translational regulation mechanism that “fine-tunes” the timing of neurogenesis, coordinating the correct emergence ofinterneurons from transcriptionally pre-fated early postnatal precursors (Chapter 5), in addition to characterizing a novel neuroprotectant promoting survival by suppressing the degeneration of peripheral neurons and potently protecting axonal mitochondria (Chapter 4). Postnatal precursors which possess multi-lineage potency and the ability to renew long-term, are a continuous source of neuronal progeny for tissue formation and repair, and must balance their maintenance through self-renewal, expansion of their pools through proliferation, and the need to generate progeny through differentiation. In Chapter 5 of this thesis, I demonstrate that postnatal precursors are “pre-fated”, expressing neuronal differentiation instructing specifier transcripts, and that a 4E-T-based regulatory mechanism involving translational repression modulates protein synthesis levels of these mRNA targets, controlling timely neurogenesis. Established peripheral neurons and their axonal projections need to then be preserved for the lifetime of the organism to ensure proper circuit function. One goal of the work presented in this thesis is to identify safe-in-man drugs that can block or delay axon degeneration, and to use these drugs to characterize new degeneration pathways. To this end, the work described in Chapter 4 describes and identifies the multikinase inhibitor Foretinib as being protective in sympathetic, sensory and motor neurons across multiple degeneration paradigms. Thus, my thesis traces the trajectory of neurons in two main aspects of neurobiology: from onset of fate commitment and appropriate neuronal lineage acquisition, to maintenance and protection in maturity once neurons integrate into circuits, highlighting the consequences to the organism in the case of aberration in either process.

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