New discovery in retinoic acid regulation of BMP signaling pathway

The research team led by Prof. Naihe Jing from SIBCB recently discovered that retinoic acid (RA) regulates bone morphogenic protein (BMP) signal duration by promoting the degradation of phosphorylated Smad1.

 

BMP is a subfamily of cytokines of the TGF-β superfamily which play key roles in regulating a wide range of biological responses during embryonic development and adult tissue homeostasis. Deregulation of BMP signaling has been associated with developmental defects, carcinogenesis, and other diseases.

 

The proper function of 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. In the study, the researchers 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. Their results reveal a mechanism by which RA suppresses BMP signaling through regulation of pSmad1 stability.

 

This work was supported by grants from the Ministry of Science and Technology of China, the National Natural Science Foundation of China, the Chinese Academy of Sciences, and the Science and Technology Commission of Shanghai Municipality.