Neogenin Promotes BMP2 Activation of YAP and Smad1 and Enhances Astrocytic Differentiation in Developing Mouse Neocortex.

Abstract

UNLABELLED:

Neogenin, a DCC (deleted in colorectal cancer) family receptor, is highly expressed in neural stem cells (NSCs). However, its function in NSCs remains to be explored. Here we provide in vitro and in vivo evidence for neogenin's function in NSCs to promote neocortical astrogliogenesis, but not self-renewal or neural differentiation. Mechanistically, neogenin in neocortical NSCs was required for BMP2 activation of YAP (yes associated protein). The active/nuclear YAP stabilized phospho-Smad1/5/8 and was necessary for BMP2 induction of astrocytic differentiation. Deletion of yap in mouse neocortical NSCs caused a similar deficit in neocortical astrogliogenesis as that in neogenin mutant mice. Expression of YAP in neogenin mutant NSCs diminished the astrocytic differentiation deficit in response to BMP2. Together, these results reveal an unrecognized function of neogenin in increasing neocortical astrogliogenesis, and identify a pathway of BMP2-neogenin-YAP-Smad1 for astrocytic differentiation in developing mouse neocortex.

SIGNIFICANCE STATEMENT:

Astrocytes, a major type of glial cells in the brain, play important roles in modulating synaptic transmission and information processing, and maintaining CNS homeostasis. The abnormal astrocytic differentiation during development contributes to dysfunctions of synaptic plasticity and neuropsychological disorders. Here we provide evidence for neogenin's function in regulation of the neocortical astrocyte differentiation during mouse brain development. We also provide evidence for the necessity of neogenin in BMP2/Smad1-induced astrocyte differentiation through YAP. Thus, our findings identify an unrecognized function of neogenin in mouse neocortical astrocyte differentiation, and suggest a signaling pathway, BMP2-neogenin-YAP-Smad1, underlying astrogliogenesis in developing mouse neocortex.

• Authors: Zhihui Huang, Dong Sun, Jin-Xia Hu, Fu-Lei Tang, Dae-Hoon Lee, Ying Wang, Guoqing Hu, Xiao-Juan Zhu, Jiliang Zhou, Lin Mei, Wen-Cheng Xiong
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 36 Issue 21 Pg. 5833-49 (05 25 2016) ISSN: 1529-2401 [Electronic] United States
• PMID: 27225772 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 the authors 0270-6474/16/365833-17$15.00/0.

Chemical References

• Adaptor Proteins, Signal Transducing
• Bmp2 protein, mouse
• Bone Morphogenetic Protein 2
• Cell Cycle Proteins
• Membrane Proteins
• Phosphoproteins
• Smad1 Protein
• Smad1 protein, mouse
• YAP-Signaling Proteins
• Yap1 protein, mouse
• neogenin

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Astrocytes (cytology, physiology)
• Bone Morphogenetic Protein 2 (metabolism)
• Cell Cycle Proteins
• Cell Differentiation (physiology)
• Cells, Cultured
• Female
• Male
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neocortex (cytology, physiology)
• Neurogenesis (physiology)
• Phosphoproteins (metabolism)
• Smad1 Protein (metabolism)
• Up-Regulation (physiology)
• YAP-Signaling Proteins