The existence of neural stem cells in the adult central nervous system (CNS) of all mammals, including humans, raises the possibility to self-replace damaged or lost neurons by activation of endogenous neural stem cells or transplantation of in vitro expanded stem cells and their progeny derived from the same person. For the full potential of adult neural stem cells to be realized, we need to identify the origin and source of adult neural stem cells, to understand the mechanisms underlying their proliferation, fate determination, and importantly in the case of neuronal lineages, to characterize their functional properties. In the intact mammalian CNS, active neurogenesis only occurs in discrete regions with mostly gliogenesis in other regions. Multipotent neural progenitors, however, can be isolated from both neurogenic and non-neurogenic regions. Since neurological diseases and injury occur in diverse regions of the CNS, including non-neurogenic regions, it is important to determine whether endogenous adult neural progenitors only exist in neurogenic regions or they are widely distributed and their neurogenic potentials are limited by their local environment. It is also important to determine whether in vitro expanded neural progenitors derived from different regions of the adult CNS behavior exhibit similar properties. Specifically, we need to understand whether cell-intrinsic differences between neural progenitors from different regions of the adult CNS, especially from non-neurogenic regions, (1) will influence their response to extrinsic stimulations for differentiation and maturation, and (2) will limit their capacity to acquire full spectrum of functional properties of mature CNS neurons. We have established multipotent clonal lines of adult neural progenitors derived from different regions of the adult CNS and developed methods to investigate their fate determination and measure their functional and electrophysiological properties. In this project, we propose to use adult neural progenitors from hippocampus (neurogenic region) and spinal cord (non-neurogenic region) as examples to examine the fate specification and maturation of in vitro expanded neural progenitors and the underlying molecular mechanisms. In particular, we will characterize the functional properties of neuronal progeny of different adult neural progenitors with immunocytochemistry, electron microscopy, FM imaging and electrophysiology. Finally, we will determine the intrinsic neurogenic potentials of endogenous progenitors of adult spinal cord by a set of transplantation studies

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047344-05
Application #
7263911
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Owens, David F
Project Start
2003-09-30
Project End
2008-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$358,502
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Shi, Hailing; Zhang, Xuliang; Weng, Yi-Lan et al. (2018) m6A facilitates hippocampus-dependent learning and memory through YTHDF1. Nature 563:249-253
Beckervordersandforth, Ruth; Ebert, Birgit; Schäffner, Iris et al. (2017) Role of Mitochondrial Metabolism in the Control of Early Lineage Progression and Aging Phenotypes in Adult Hippocampal Neurogenesis. Neuron 93:1518
Shao, Lisha; Lu, Binyan; Wen, Zhexing et al. (2017) Disrupted-in-Schizophrenia-1 (DISC1) protein disturbs neural function in multiple disease-risk pathways. Hum Mol Genet 26:2634-2648
Su, Yijing; Shin, Jaehoon; Zhong, Chun et al. (2017) Neuronal activity modifies the chromatin accessibility landscape in the adult brain. Nat Neurosci 20:476-483
Yoon, Ki-Jun; Ringeling, Francisca Rojas; Vissers, Caroline et al. (2017) Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation. Cell 171:877-889.e17
Yao, Bing; Christian, Kimberly M; He, Chuan et al. (2016) Epigenetic mechanisms in neurogenesis. Nat Rev Neurosci 17:537-49
Qian, Xuyu; Nguyen, Ha Nam; Song, Mingxi M et al. (2016) Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure. Cell 165:1238-1254
Xu, Miao; Lee, Emily M; Wen, Zhexing et al. (2016) Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat Med 22:1101-1107
Tang, Hengli; Hammack, Christy; Ogden, Sarah C et al. (2016) Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth. Cell Stem Cell 18:587-90
Zhang, Hongsheng; Kang, Eunchai; Wang, Yaqing et al. (2016) Brain-specific Crmp2 deletion leads to neuronal development deficits and behavioural impairments in mice. Nat Commun 7:

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