Glial cells comprise approximately 80% of the cellular constituency of the adult central nervous system (CNS) and support a vast array of physiological roles essential to CNS function, including myelination, synapse formation, neurotransmission, and formation of the blood-brain barrier. Recent studies of glial development have documented many of the mechanisms that control the terminal differentiation and maturation of the astrocyte and oligodendrocyte sublineages. However, our knowledge of the preceding molecular processes that control the initiation of gliogenesis from multipotent neural stem cells in vivo remains rudimentary. The overriding goal of this proposal is to elucidate the molecular mechanisms that govern the initiation of gliogenesis. Recently we found that the Sox9/NFIA relationship represents a crucial regulatory node during neural stem cell commitment to the glial lineage, therefore dissection of their upstream regulatory events and downstream transcriptional networks will provide novel insight into the regulatory processes that control earl gliogenesis. Our preliminary studies on the upstream regulatory events in gliogenesis suggest that Sox9 and Brn2 co-regulate NFIA through distinct enhancer elements that are brought together by Med12 mediated chromatin looping. Therefore in specific aim1 we will delineate how Brn2 regulates NFIA expression and whether Sox9/Brn2 collaboratively regulate NFIA induction and gliogenesis.
In specific aim2, we will perform chromatin conformation capture (3C) to determine the three-dimensional architecture of the NFIA locus and examine whether the chromatin looping factor, Med12, regulates chromatin configuration at the NFIA locus and collaborates with Sox9/Brn2 to regulate NFIA induction. To identify key downstream events, we combined ChIP-Seq and gene expression profiling on FACS isolated, CD15+ spinal cord progenitors to dissociate the Sox9/NFIA transcriptional networks during gliogenesis.
In specific aim3, we will validate and functionally analyze a set of candidate gliogenic targets identified in this screen and, in conjunction with our studies during gliogenesis, extend our ChIP-Seq analysis to earlier developmental stages to identify Sox9-specific targets in neural stem cell populations
This project focuses on the molecular processes that regulate the generation of glial cells (oligodendrocytes and astrocytes) from neural stem cells in the developing CNS. Glial cells have been implicated in a host of neurological disorders, including Multiple Sclerosis (MS), Rett's Syndrome, and Glioblastoma (GBM)
|Zhu, Wenyi; Krishna, Saritha; Garcia, Cristina et al. (2017) Daam2 driven degradation of VHL promotes gliomagenesis. Elife 6:|
|Glasgow, Stacey M; Carlson, Jeffrey C; Zhu, Wenyi et al. (2017) Glia-specific enhancers and chromatin structure regulate NFIA expression and glioma tumorigenesis. Nat Neurosci 20:1520-1528|
|John Lin, Chia-Ching; Yu, Kwanha; Hatcher, Asante et al. (2017) Identification of diverse astrocyte populations and their malignant analogs. Nat Neurosci 20:396-405|
|Chaboub, Lesley S; Manalo, Jeanne M; Lee, Hyun Kyoung et al. (2016) Temporal Profiling of Astrocyte Precursors Reveals Parallel Roles for Asef during Development and after Injury. J Neurosci 36:11904-11917|
|Garcia, Isabella; Bhullar, Paramjit K; Tepe, Burak et al. (2016) Local corticotropin releasing hormone (CRH) signals to its receptor CRHR1 during postnatal development of the mouse olfactory bulb. Brain Struct Funct 221:1-20|
|Lee, Hyun Kyoung; Chaboub, Lesley S; Zhu, Wenyi et al. (2015) Daam2-PIP5K is a regulatory pathway for Wnt signaling and therapeutic target for remyelination in the CNS. Neuron 85:1227-43|
|Lee, Hyun Kyoung; Laug, Dylan; Zhu, Wenyi et al. (2015) Apcdd1 stimulates oligodendrocyte differentiation after white matter injury. Glia 63:1840-9|
|Lee, Jun Sung; Xiao, Jiping; Patel, Parita et al. (2014) A novel tumor-promoting role for nuclear factor IA in glioblastomas is mediated through negative regulation of p53, p21, and PAI1. Neuro Oncol 16:191-203|
|Glasgow, Stacey M; Zhu, Wenyi; Stolt, C Claus et al. (2014) Mutual antagonism between Sox10 and NFIA regulates diversification of glial lineages and glioma subtypes. Nat Neurosci 17:1322-9|
|Gallo, Vittorio; Deneen, Benjamin (2014) Glial development: the crossroads of regeneration and repair in the CNS. Neuron 83:283-308|
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