(Project 3) Human brain complexity is considered unique, yet the genesis of many neuronal and glial sub-types and their migration and integration into functional circuits in neonates remains poorly understood. Moreover, these processes are likely disrupted in newborn hypoxic neurological injuries. Project 3 will establish HIF pathway activation in term infants with hypoxic-ischemic encephalopathy (HIE) and cell-intrinsic HIF pathway functions during interneuron (IN) and oligodendrocyte (OL) ontogeny in developing animal systems.
The Specific Aims and hypotheses to be tested are: ? Aim1 is to determine activation of the HIF pathway in """"""""Regions of Interest (ROIs)"""""""" defined in Projects 1, 2 and prior published work that include neural progenitors, oligodendroglia and late-migrating neurons in the term infant brain with HIE and controls. Hypothesis: HIE results in HIF pathway activation in human brain germinal zones and developing neuron and OL progenitors. ? Aim 2 is to determine functions of the HIF pathway in regulation of interneuron proliferation, migration and/or differentiation. Hypothesis: Interneuron cell-type specific conditional activation (using floxed VHL) or loss-of-function (using floxed HIF1?, HIF2?-null alleles) will result in abnormal precursor allocation, migration and/or differentiation. ? Aim 3 is to determine functions for HIF pathway in regulation of oligodendrocyte proliferation, migration and/or differentiation at pre- and post-natal stages. Hypothesis: Oligodendrocyte cell-type specific conditional activation (using floxed VHL) or loss-of-function (using floxed HIF1?, HIF2?-null alleles) will result in abnormal precursor allocation, migration and/or differentiation. Further, we will use explant approaches in transgenic mice and the ferret brain to answer these questions and determine conserved mechanisms of development and the injury response.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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University of California San Francisco
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Shiow, Lawrence R; Favrais, Geraldine; Schirmer, Lucas et al. (2017) Reactive astrocyte COX2-PGE2 production inhibits oligodendrocyte maturation in neonatal white matter injury. Glia 65:2024-2037
Watanabe, Momoko; Buth, Jessie E; Vishlaghi, Neda et al. (2017) Self-Organized Cerebral Organoids with Human-Specific Features Predict Effective Drugs to Combat Zika Virus Infection. Cell Rep 21:517-532
Sabo, Jennifer K; Heine, Vivi; Silbereis, John C et al. (2017) Olig1 is required for noggin-induced neonatal myelin repair. Ann Neurol 81:560-571
Lindquist, Robert A; Guinto, Cristina D; Rodas-Rodriguez, Jose L et al. (2016) Identification of proliferative progenitors associated with prominent postnatal growth of the pons. Nat Commun 7:11628
Tsai, Hui-Hsin; Niu, Jianqin; Munji, Roeben et al. (2016) Oligodendrocyte precursors migrate along vasculature in the developing nervous system. Science 351:379-84
Paredes, Mercedes F; Sorrells, Shawn F; Garcia-Verdugo, Jose M et al. (2016) Brain size and limits to adult neurogenesis. J Comp Neurol 524:646-64
Paredes, Mercedes F; James, David; Gil-Perotin, Sara et al. (2016) Extensive migration of young neurons into the infant human frontal lobe. Science 354:
Nobuta, Hiroko; Cilio, Maria Roberta; Danhaive, Olivier et al. (2015) Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome. Acta Neuropathol 130:171-83
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
Tate, Matthew C; Lindquist, Robert A; Nguyen, Thuhien et al. (2015) Postnatal growth of the human pons: a morphometric and immunohistochemical analysis. J Comp Neurol 523:449-62

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