title: Neurotrophic Factor-α1: A Key Wnt-β-Catenin Dependent Anti-Proliferation Factor and ERK-Sox9 Activated Inducer of Embryonic Neural Stem Cell Differentiation to Astrocytes in Neurodevelopment.
abstract: 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-α1, 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 β-catenin. NF-α1 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-α1-knockout mice showed decreased astrocyte numbers compared to wild-type mice, which was rescued by treatment with NF-α1. In vivo, immunocytochemistry of brain sections and Western blot analysis of neocortex of mice showed a gradual increase of NF-α1 expression from E14.5 to P1 and a surge of GFAP expression at P1, the time of increase in astrogenesis. Importantly, NF-α1-Knockout mice showed ∼49% fewer GFAP positive astrocytes in the neocortex compared to WT mice at P1. Thus, NF-α1 is critical for regulating antiproliferation and cell fate determination, through differentiating embryonic stem cells to GFAP-positive astrocytes for normal neurodevelopment. Stem Cells 2017;35:557-571.
authors.affiliation: Section on Cellular Neurobiology, Bethesda, Maryland, USA.
authors.forename: Prabhuanand
authors.initials: P
authors.lastname: Selvaraj
authors.affiliation: Section on Cellular Neurobiology, Bethesda, Maryland, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Unit on Developmental Neurogenetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Cheol
authors.initials: C
authors.lastname: Lee
authors.affiliation: Section on Cellular Neurobiology, Bethesda, Maryland, USA.
authors.forename: Saravana R K
authors.initials: SR
authors.lastname: Murthy
authors.affiliation: Section on Cellular Neurobiology, Bethesda, Maryland, USA.
authors.forename: Niamh X
authors.initials: NX
authors.lastname: Cawley
authors.affiliation: Department of Epidemiology and Public Health and Anatomy and Neurobiology, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Lane
authors.affiliation: Department of Epidemiology and Public Health and Anatomy and Neurobiology, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Istvan
authors.initials: I
authors.lastname: Merchenthaler
authors.affiliation: Unit on Developmental Neurogenetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Sohyun
authors.initials: S
authors.lastname: Ahn
authors.affiliation: Section on Cellular Neurobiology, Bethesda, Maryland, USA.
authors.forename: Y Peng
authors.initials: YP
authors.lastname: Loh
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism; D043423:Carboxypeptidase H / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D047108:Embryonic Development; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000378:metabolism*; D009420:Nervous System / Q000196:embryology; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D009414:Nerve Growth Factors; D055758:SOX9 Transcription Factor; D051153:Wnt Proteins; D051176:beta Catenin; D048049:Extracellular Signal-Regulated MAP Kinases; D043423:Carboxypeptidase H
keywords: Astrocytes; Carboxypeptidase E; Neurotrophic factor-α1; Stem cell; Wnt pathway