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

Stem Cells. 2017 Mar;35(3):557-571. doi: 10.1002/stem.2511. Epub 2016 Oct 26.


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.

Keywords: Astrocytes; Carboxypeptidase E; Neurotrophic factor-α1; Stem cell; Wnt pathway.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Astrocytes / cytology*
  • Astrocytes / metabolism
  • Carboxypeptidase H / metabolism*
  • Cell Differentiation*
  • Cell Proliferation
  • Embryonic Development
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • Glial Fibrillary Acidic Protein / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Growth Factors / metabolism*
  • Nervous System / embryology
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / metabolism
  • SOX9 Transcription Factor / metabolism*
  • Spheroids, Cellular / cytology
  • Spheroids, Cellular / metabolism
  • Time Factors
  • Wnt Proteins / metabolism
  • Wnt Signaling Pathway*
  • beta Catenin / metabolism


  • Glial Fibrillary Acidic Protein
  • Nerve Growth Factors
  • SOX9 Transcription Factor
  • Wnt Proteins
  • beta Catenin
  • Extracellular Signal-Regulated MAP Kinases
  • Carboxypeptidase H