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 early 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

Public Health Relevance

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)

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01NS071153-05
Application #
8627334
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Lavaute, Timothy M
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77030
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
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
Gallo, Vittorio; Deneen, Benjamin (2014) Glial development: the crossroads of regeneration and repair in the CNS. Neuron 83:283-308
Chaboub, Lesley S; Deneen, Benjamin (2013) Astrocyte form and function in the developing central nervous system. Semin Pediatr Neurol 20:230-5
Molofsky, Anna V; Glasgow, Stacey M; Chaboub, Lesley S et al. (2013) Expression profiling of Aldh1l1-precursors in the developing spinal cord reveals glial lineage-specific genes and direct Sox9-Nfe2l1 interactions. Glia 61:1518-32
John Lin, Chia-Ching; Deneen, Benjamin (2013) Astrocytes: the missing link in neurologic disease? Semin Pediatr Neurol 20:236-41
Glasgow, Stacey M; Laug, Dylan; Brawley, Vita S et al. (2013) The miR-223/nuclear factor I-A axis regulates glial precursor proliferation and tumorigenesis in the CNS. J Neurosci 33:13560-8
Kang, Peng; Lee, Hyun Kyoung; Glasgow, Stacey M et al. (2012) Sox9 and NFIA coordinate a transcriptional regulatory cascade during the initiation of gliogenesis. Neuron 74:79-94
Lee, Hyun Kyoung; Deneen, Benjamin (2012) Daam2 is required for dorsal patterning via modulation of canonical Wnt signaling in the developing spinal cord. Dev Cell 22:183-96