Retinoic acid regulates bone morphogenic protein signal duration by promoting the degradation of phosphorylated Smad1.
The proper function of the bone morphogenic protein (BMP) pathway during embryonic development and organ maintenance requires its communication with other signaling pathways. Unlike the well-documented regulation of the BMP pathway by FGF/MAPK and Wnt/GSK3 signals, cross-talk between BMP/Smad and retinoic acid (RA)/RA receptor (RAR) pathways is poorly understood. Here, we show that RA represses BMP signal duration by reducing the level of phosphorylated Smad1 (pSmad1). Through its nuclear receptor-mediated transcription, RA enhances the interaction between pSmad1 and its ubiquitin E3 ligases, thereby promoting pSmad1 ubiquitination and proteasomal degradation. This regulation depends on the RA-increased Gadd45 expression and MAPK activation. During the neural development in chicken embryo, the RA/RAR pathway also suppresses BMP signaling to antagonize BMP-regulated proliferation and differentiation of neural progenitor cells. Furthermore, this cross-talk between RA and BMP pathways is involved in the proper patterning of dorsal neural tube of chicken embryo. Our results reveal a mechanism by which RA suppresses BMP signaling through regulation of pSmad1 stability.
Sheng
Nengyin
N
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Xie
Zhihui
Z
Wang
Chen
C
Bai
Ge
G
Zhang
Kejing
K
Zhu
Qingqing
Q
Song
Jianguo
J
Guillemot
Francois
F
Chen
Ye-Guang
YG
Lin
Anning
A
Jing
Naihe
N
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002642:Chick Embryo; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D047108:Embryonic Development / Q000502:physiology; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D054259:Neural Tube / Q000196:embryology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D000097642:GADD45 Proteins
D019485:Bone Morphogenetic Proteins; D018797:Cell Cycle Proteins; D004815:Epidermal Growth Factor; D038362:Glycogen Synthase Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex; D018168:Receptors, Retinoic Acid; D051898:Smad1 Protein; D014212:Tretinoin; D044767:Ubiquitin-Protein Ligases; D051153:Wnt Proteins; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins; C497401:Smad1 protein, mouse