title: RNF12 controls embryonic stem cell fate and morphogenesis in zebrafish embryos by targeting Smad7 for degradation.
abstract: 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.
authors.affiliation: Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands. l.zhang@lumc.nl
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.forename: Huizhe
authors.initials: H
authors.lastname: Huang
authors.forename: Fangfang
authors.initials: F
authors.lastname: Zhou
authors.forename: Joost
authors.initials: J
authors.lastname: Schimmel
authors.forename: Cristina Gontan
authors.initials: CG
authors.lastname: Pardo
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhang
authors.forename: Tahsin Stefan
authors.initials: TS
authors.lastname: Barakat
authors.forename: Kelly-Ann
authors.initials: KA
authors.lastname: Sheppard
authors.forename: Craig
authors.initials: C
authors.lastname: Mickanin
authors.forename: Jeff A
authors.initials: JA
authors.lastname: Porter
authors.forename: Alfred C O
authors.initials: AC
authors.lastname: Vertegaal
authors.forename: Hans
authors.initials: H
authors.lastname: van Dam
authors.forename: Joost
authors.initials: J
authors.lastname: Gribnau
authors.forename: Chris X
authors.initials: CX
authors.lastname: Lu
authors.forename: Peter
authors.initials: P
authors.lastname: ten Dijke
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D004625:Embryo, Nonmammalian / Q000166:cytology* / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D054262:Gastrulation / Q000235:genetics; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D059748:Proteolysis; D015398:Signal Transduction; D051906:Smad7 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*
chemical_list: D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; D029961:Zebrafish Proteins; C497810:smad7 protein, zebrafish; C492370:RLIM protein, human; D044767:Ubiquitin-Protein Ligases; C574637:rlim protein, zebrafish