(Project 2) The overall goals of Project 2 are to study the origins and later development of human oligodendrocyte precursor cells (OPCs) in fetal human cortex during 20-40 weeks gestation age (GA). We will study processes of OPC proliferation, the nature of their migratory behavior and differentiation in situ the relationship to the outer subventricular zone (oSVZ);a germinal zone present in 3rd trimester human brain that may account for significant gliogenesis.
Specific aims i nclude a detailed exploration of OPC lineage ontogeny in human cortex, based on anatomical and immunolabeling marker analysis of both acutely harvested cortical tissue and specimens from the Core B tissue bank. We will perform dynamic imaging of proliferation in fetal slice cultures to test our hypothesis that a transit amplifying OPC undergoes multiple rounds of symmetric divisions to provide the very large number of OL cells needed to myelinate axons in human cortex. We also plan to develop the ferret as an animal model of OL development with the expectation that oligodendrogenesis will mimic that of the developing human brain but on a compressed timescale. We will use the fetal gyrencephalic ferret cortex that can be manipulated experimentally;so that the combined study of human and ferret will provide a more complete understanding of OL development and maturation. Finally, We will use both human and ferret cortex in complementary fashion to determine if the developing ferret cortex can be used to model the effects of hypoxia in the preterm human. We will test the hypothesis that low O2 tension promotes fetal oligodendrocyte proliferation and inhibits differentiation, while high O2 inhibits oligodendrocyte proliferation and promotes differentiation. White matter injury is associated with cerebral palsy in premature infants, but the specific effects of O2 tension on the cell lineage leading to the production of a myelinating oligodendrocyte has not been well defined in animals or humans. The results may eventually help us better understand the causes of and guide the clinical management for premature newborn infants at risk for these disorders.
|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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