BMP2-SMAD Signaling Represses the Proliferation of Embryonic Neural Stem Cells through YAP
- Minghui Yao1,2,*,
- Yadong Wang1,4,*,
- Peng Zhang1,
- Hong Chen1,
- Zhiheng Xu2,
- Jianwei Jiao3, and
- Zengqiang Yuan1
- 1State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics,
- 2State Key Laboratory of Developmental Biology, Institute of Genetic and Developmental Biology, and
- 3State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China, and
- 4University of Chinese Academy of Sciences, Beijing 100049, China
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Author contributions: M.Y., Y.W., P.Z., and Z.Y. designed research; M.Y., Y.W., P.Z., and H.C. performed research; Z.X. and J.J. contributed unpublished reagents/analytic tools; M.Y., Y.W., P.Z., Z.X., J.J., and Z.Y. analyzed data; M.Y., Y.W., P.Z., and Z.Y. wrote the paper.
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↵*M.Y. and Y.W. contributed equally to this work.
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.
- Received February 3, 2014.
- Revision received June 14, 2014.
- Accepted July 8, 2014.
- Copyright © 2014 the authors 0270-6474/14/3412039-10$15.00/0
