title: Neogenin Promotes BMP2 Activation of YAP and Smad1 and Enhances Astrocytic Differentiation in Developing Mouse Neocortex.
abstract: 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.
  
  
  
  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.affiliation: Department of Neuroscience & Regenerative Medicine and Department of Neurology and Charlie Norwood Veterans Administration Medical Center, Augusta, Georgia 30912, Institute of Hypoxia Medicine and Institute of Neuroscience, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Neuroscience & Regenerative Medicine and Department of Neurology and Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Cytology and Genetics, Northeast Normal University, Changchun, Jilin 130024, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Neuroscience & Regenerative Medicine and Department of Neurology and Charlie Norwood Veterans Administration Medical Center, Augusta, Georgia 30912, Institute of Nervous System Diseases, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China, and.
authors.forename: Jin-Xia
authors.initials: JX
authors.lastname: Hu
authors.affiliation: Department of Neuroscience & Regenerative Medicine and Department of Neurology and Charlie Norwood Veterans Administration Medical Center, Augusta, Georgia 30912.
authors.forename: Fu-Lei
authors.initials: FL
authors.lastname: Tang
authors.affiliation: Department of Neuroscience & Regenerative Medicine and Department of Neurology and.
authors.forename: Dae-Hoon
authors.identifier: 0000-0002-7930-2938
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Neuroscience & Regenerative Medicine and Department of Neurology and Research Center of Blood Transfusion Medicine, Key Laboratory of Laboratory Medicine (Wenzhou Medical University), Ministry of Education, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Hu
authors.affiliation: Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Cytology and Genetics, Northeast Normal University, Changchun, Jilin 130024, China.
authors.forename: Xiao-Juan
authors.identifier: 0000-0001-8386-8064
authors.initials: XJ
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
authors.forename: Jiliang
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Neuroscience & Regenerative Medicine and Department of Neurology and Charlie Norwood Veterans Administration Medical Center, Augusta, Georgia 30912.
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
authors.affiliation: Department of Neuroscience & Regenerative Medicine and Department of Neurology and Charlie Norwood Veterans Administration Medical Center, Augusta, Georgia 30912, wxiong@augusta.edu.
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Xiong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000502:physiology*; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019579:Neocortex / Q000166:cytology / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism*; D051898:Smad1 Protein / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; C091279:neogenin
keywords: BMP2; YAP; astrocytes; differentiation; neogenin