title: BMP2-SMAD signaling represses the proliferation of embryonic neural stem cells through YAP.
abstract: Previous studies have shown that the Hippo pathway effector yes-associated protein (YAP) plays an important role in maintaining stem cell proliferation. However, the precise molecular mechanism of YAP in regulating murine embryonic neural stem cells (NSCs) remains largely unknown. Here, we show that bone morphogenetic protein-2 (BMP2) treatment inhibited the proliferation of mouse embryonic NSCs, that YAP was critical for mouse NSC proliferation, and that BMP2 treatment-induced inhibition of mouse NSC proliferation was abrogated by YAP knockdown, indicating that the YAP protein mediates the inhibitory effect of BMP2 signaling. Additionally, we found that BMP2 treatment reduced YAP nuclear translocation, YAP-TEAD interaction, and YAP-mediated transactivation. BMP2 treatment inhibited YAP/TEAD-mediated Cyclin D1 (ccnd1) expression, and knockdown of ccnd1 abrogated the BMP2-mediated inhibition of mouse NSC proliferation. Mechanistically, we found that Smad1/4, effectors of BMP2 signaling, competed with YAP for the interaction with TAED1 and inhibited YAP's cotranscriptional activity. Our data reveal mechanistic cross talk between BMP2 signaling and the Hippo-YAP pathway in murine NSC proliferation, which may be exploited as a therapeutic target in neurodegenerative diseases and aging.
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, State Key Laboratory of Developmental Biology, Institute of Genetic and Developmental Biology, and.
authors.forename: Minghui
authors.initials: M
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Developmental Biology, Institute of Genetic and Developmental Biology, and.
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China, and.
authors.forename: Jianwei
authors.identifier: http://orcid.org/0000-0002-7893-0721
authors.initials: J
authors.lastname: Jiao
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, zqyuan@ibp.ac.cn.
authors.forename: Zengqiang
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism*; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D055396:Bone Morphogenetic Protein 2; C530105:Ccnd1 protein, mouse; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D000091262:TEA Domain Transcription Factors; C083215:Tead1 protein, mouse; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D019938:Cyclin D1
keywords: BMP2; YAP; hippo; neural stem cell; proliferation; transcription