西亚试剂：RNF12 Controls Embryonic Stem Cell Fate and Morphogenesis i

RNF12 Controls Embryonic Stem Cell Fate and Morphogenesis in Zebrafish Embryos by Targeting Smad7 for Degradation

Long Zhang， Huizhe Huang， FangFang Zhou， Joost Schimmel， Cristina Gontan Pardo， Tingting Zhang， Tahsin Stefan Barakat， Kelly-Ann Sheppard， Craig Mickanin， Jeff A. Porter， Alfred C.O. Vertegaal， Hans van Dam1， Joost Gribnau， Chris X. Lu， Peter ten Dijke，

1 Department of Molecular Cell Biology and Centre for Biomedical Genetics， Leiden University Medical Center， Postbus 9600 2300 RC Leiden， The Netherlands

2 Faculty of Basic Medical Sciences， Chonqing Medical University， Medical College Road 1， 400016 Chongqing， China

3 Department of Reproduction and Development， Erasmus MC， University Medical Center， PO Box 2040， 3000 CA Rotterdam， The Netherlands

4 Novartis Institutes for Biomedical Research， 250 Massachusetts Avenue， Cambridge， MA 02139， USA

Summary

TGF-β members are of key importance during embryogenesis and tissue homeostasis. Smad7 is a potent antagonist of TGF-β family/Smad-mediated responses， but the regulation of Smad7 activity is not well understood. We identified the RING domain-containing E3 ligase RNF12 as a critical component of TGF-β signaling. Depletion of RNF12 dramatically reduced TGF-β/Smad-induced effects in mammalian cells， whereas ectopic expression of RNF12 strongly enhanced these responses. RNF12 specifically binds to Smad7 and induces its polyubiquitination and degradation. Smad7 levels were increased in RNF12-deficient mouse embryonic stem cells， resulting in mitigation of both BMP-mediated repression of neural induction and activin-induced anterior mesoderm formation. RNF12 also antagonized Smad7 during Nodal-dependent and BMP-dependent signaling and morphogenic events in early zebrafish embryos. The gastrulation defects induced by ectopic and depleted Smad7 were rescued in part by RNF12 gain and loss of function， respectively. These findings demonstrate that RNF12 plays a critical role in TGF-β family signaling.

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