日前，荷兰研究人员在线发表了题为《RNF12 Controls Embryonic Stem Cell Fate and Morphogenesis in Zebrafish Embryos by Targeting Smad7 for Degradation》研究论文，发现了控制胚胎干细胞命运和形态发生的机制，并证明RNF12在TNF-β家族信号转导中起到决定性作用。该研究论文发表在Molecular Cell上。
Smad7蛋白是一个调节TNF-β家族/Smad7反应的拮抗剂，但其调节机制还不明白。
首先，我们确定编码RING结构域的E3连接酶RNF12为TNF-β信号通路中的决定性组成成分。RNF12的消耗显著地降低TNF-β家族/Smad7诱导的效应，相反，RNF12的异常表达强烈地增强TNF-β家族/Smad7诱导的效应。
其次，在斑马鱼胚胎早期，Nodal依赖和BMP依赖的信号转导和形态发生事件时，RNF12与Smad7是对抗的。由Smad7消耗或异常引起的原肠胚形成缺陷可以通过RNF12功能的获得或缺失而恢复。
研究发现造成以上事件的机制是RNF12特异地与Smad7结合并引起其多泛素化而降解。这些发现证明RNF12在TNF-β家族信号转导中起到决定性作用。（生物谷 Bioon.com)
doi.org/10.1016/j.molcel.2012.04.003
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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.
