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

• Published in: Molecular cell 2012-06, Vol.46 (5), p.650-661
• Main Authors: Zhang, Long, Huang, Huizhe, Zhou, FangFang, Schimmel, Joost, Pardo, Cristina Gontan, Zhang, Tingting, Barakat, Tahsin Stefan, Sheppard, Kelly-Ann, Mickanin, Craig, Porter, Jeff A., Vertegaal, Alfred C.O., van Dam, Hans, Gribnau, Joost, Lu, Chris X., ten Dijke, Peter
• Format: Article
• Language: English
• Subjects: Animals; antagonists; Cell Differentiation - genetics; Danio rerio; Embryo, Nonmammalian - cytology; Embryo, Nonmammalian - metabolism; embryogenesis; embryonic stem cells; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Freshwater; gastrulation; Gastrulation - genetics; homeostasis; Humans; Jurkat Cells; ligases; Mice; morphogenesis; Proteolysis; Signal Transduction; Smad7 Protein - metabolism; transforming growth factor beta; Transforming Growth Factor beta - metabolism; ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitin-Protein Ligases - physiology; Zebrafish - embryology; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism; Zebrafish Proteins - physiology
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2012.04.003

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. ► RNF12 E3 ubiquitin ligase is a critical positive regulator of TGF-β family signaling ► RNF12 induces polyubiquitination and degradation of Smad7 ► RNF12 controls BMP and activin-induced differentiation responses in ESCs ► RNF12 antagonizes Smad7 function in zebrafish embryos