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

Long, Zhang and HuiZhe, Huang and Fang Fang, Zhou and Sheppard, Kelly-Ann and Mickanin, Craig and Porter, Jeffrey and Hans, van Dam and Gribnau, Joost and Lu, Chris and Peter, ten Dijke (2012) RNF12 Controls Embryonic Stem Cell Fate and Morphogenesis in Zebrafish Embryos by Targeting Smad7 for Degradation. Molecular Cell, 46 (5). pp. 650-661. ISSN 1097-2765

Abstract

TGF-b members are of key importance during
embryogenesis and tissue homeostasis. Smad7 is
a potent antagonist of TGF-b 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-b signaling. Depletion of RNF12
dramatically reduced TGF-b/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 activininduced
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-b family signaling.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/3953

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