title: YAP stabilizes SMAD1 and promotes BMP2-induced neocortical astrocytic differentiation.
abstract: ‪YAP (yes-associated protein), a key transcriptional co-factor that is negatively regulated by the Hippo pathway, is crucial for the development and size control of multiple organs, including the liver. However, its role in the brain remains unclear. Here, we provide evidence for YAP regulation of mouse neocortical astrocytic differentiation and proliferation. YAP was undetectable in neurons, but selectively expressed in neural stem cells (NSCs) and astrocytes. YAP in NSCs was required for neocortical astrocytic differentiation, with no apparent role in self-renewal or neural differentiation. However, YAP in astrocytes was necessary for astrocytic proliferation. Yap (Yap1) knockout, Yap(nestin) conditional knockout and Yap(GFAP) conditional knockout mice displayed fewer neocortical astrocytes and impaired astrocytic proliferation and, consequently, death of neocortical neurons. Mechanistically, YAP was activated by BMP2, and the active/nuclear YAP was crucial for BMP2 induction and stabilization of SMAD1 and astrocytic differentiation. Expression of SMAD1 in YAP-deficient NSCs partially rescued the astrocytic differentiation deficit in response to BMP2. Taken together, these results identify a novel function of YAP in neocortical astrocytic differentiation and proliferation, and reveal a BMP2-YAP-SMAD1 pathway underlying astrocytic differentiation in the developing mouse neocortex.
authors.affiliation: Department of Neuroscience & Regenerative Medicine and Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA 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, Medical College of Georgia, Augusta, GA 30912, USA Charlie Norwood VA Medical Center, Augusta, GA 30912, USA Institute of Nervous System Diseases, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
authors.forename: Jinxia
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Neuroscience & Regenerative Medicine and Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA Charlie Norwood VA Medical Center, Augusta, GA 30912, USA.
authors.forename: Jinxiu
authors.initials: J
authors.lastname: Pan
authors.affiliation: Department of Neuroscience & Regenerative Medicine and Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA 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, GA 30912, USA.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Hu
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912, USA.
authors.forename: Jiliang
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Neuroscience & Regenerative Medicine and Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA Charlie Norwood VA Medical Center, Augusta, GA 30912, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
authors.affiliation: Department of Neuroscience & Regenerative Medicine and Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA Charlie Norwood VA Medical Center, Augusta, GA 30912, USA wxiong@gru.edu.
authors.forename: Wen-Cheng
authors.identifier: 0000-0001-9071-7598
authors.initials: WC
authors.lastname: Xiong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000066673:Cell Self Renewal / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019579:Neocortex / Q000166:cytology* / Q000196:embryology; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051898:Smad1 Protein / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D055396:Bone Morphogenetic Protein 2; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D051898:Smad1 Protein; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse
keywords: Astrocytes; BMP2; Differentiation; Proliferation; SMAD1; YAP