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Abstract
The mammalian central nervous system is the most complex organ among all the mammalian organs and we have just began understanding the highly orchestrated but nonlinear process of brain development. Brain development involves many various cellular behaviors including progenitor self-renewal, proliferation, patterning, differentiation, migration etc. My dissertation research in Dr. Wange Lu's lab has mainly focused on one core question in the field of neural development: to uncover the mechanisms regulating the cell fate specification of neural progenitor cells during brain development. My research involves the investigation of two independent but closely related aspects of this core question.
In my thesis, I have first investigated the role of an atypical Wnt receptor Ryk in regulating the cell fate choice between the neuronal differentiation and oligodendrogenesis and demonstrated that Wnt3a-Ryk-mediated signaling promotes GABAergic neuron production, while inhibiting oligodendrocyte differentiation through a Ryk intracellular domain-dependent mechanism.
Secondly, I have investigated the biological function of a histone H2A deubiquitinase MYSM1 in cortical neurogenesis. Both in vivo and in vitro analyses demonstrate that MYSM1 plays a critical role in neuronal cell fate specification without affecting the maintenance of the cortical progenitor pool. To further elucidate the underlying molecular mechanisms, a ChIP-Seq analysis of genome-wide occupancy of repressive histone mark H3K27me3 and active histone mark H3K4me2 in both wild-type and MYSM1 knockout primary neural progenitor cell culture under proliferating conditions was conducted: it shows that a group of genes regulating neuronal development exhibit a more repressive but less active chromatin status upon loss of MYSM1. This research supports the role of MYSM1 in regulating transcriptional activation of neuronal gene to facilitate the neuronal cell fate specification, likely through removing repressive histone mark H2Aub1 and cross-talk with other histone modifications.
This research is of great importance not only for our understanding about the extremely complicated establishment process of the central nervous system, but also provides a potential application for developing stem cell based therapy.
