期刊
STEM CELLS
卷 35, 期 3, 页码 557-571出版社
WILEY
DOI: 10.1002/stem.2511
关键词
Carboxypeptidase E; Neurotrophic factor-1; Astrocytes; Stem cell; Wnt pathway
资金
- Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- National Institutes of Health, USA
Embryonic neurodevelopment involves inhibition of proliferation of multipotent neural stem cells (NSCs) followed by differentiation into neurons, astrocytes and oligodendrocytes to form the brain. We have identified a new neurotrophic factor, NF-1, which inhibits proliferation and promotes differentiation of NSC/progenitors derived from E13.5 mouse cortex. Inhibition of proliferation of these cells was mediated through negatively regulating the Wnt pathway and decreasing -catenin. NF-1 induced differentiation of NSCs to astrocytes by enhancing Glial Fibrillary Acidic Protein (GFAP) expression through activating the ERK1/2-Sox9 signaling pathway. Cultured E13.5 cortical stem cells from NF-1-knockout mice showed decreased astrocyte numbers compared to wild-type mice, which was rescued by treatment with NF-1. In vivo, immunocytochemistry of brain sections and Western blot analysis of neocortex of mice showed a gradual increase of NF-1 expression from E14.5 to P1 and a surge of GFAP expression at P1, the time of increase in astrogenesis. Importantly, NF-1-Knockout mice showed approximate to 49% fewer GFAP positive astrocytes in the neocortex compared to WT mice at P1. Thus, NF-1 is critical for regulating antiproliferation and cell fate determination, through differentiating embryonic stem cells to GFAP-positive astrocytes for normal neurodevelopment.
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