title: Enhanced SMAD1 Signaling Contributes to Impairments of Early Development in CFC-iPSCs.
abstract: Cardio-facio-cutaneous (CFC) syndrome is a developmental disorder caused by constitutively active ERK signaling manifesting mainly from BRAF mutations. Little is known about the role of elevated ERK signaling in CFC syndrome during early development. Here, we show that both SMAD1 and ERK signaling pathways may contribute to the developmental defects in CFC syndrome. Induced pluripotent stem cells (iPSCs) derived from dermal fibroblasts of a CFC syndrome patient (CFC-iPSCs) revealed early developmental defects in embryoid body (EB) development, β-catenin localization, and neuronal differentiation. Both SMAD1 and ERK signalings were significantly activated in CFC-iPSCs during EB formation. Most of the β-catenin was dissociated from the membrane and preferentially localized into the nucleus in CFC-EBs. Furthermore, activation of SMAD1 signaling recapitulated early developmental defects in wild-type iPSCs. Intriguingly, inhibition of SMAD1 signaling in CFC-iPSCs rescued aberrant EB morphology, impaired neuronal differentiation, and altered β-catenin localization. These results suggest that SMAD1 signaling may be a key pathway contributing the pathogenesis of CFC syndrome during early development.
authors: Department of Biological Sciences and Center for Stem Cell Differentiation, KAIST, Daejeon, Republic of Korea.
authors: Kyu-Min
authors: KM
authors: Han
authors: Seung-Kyoon
authors: SK
authors: Kim
authors: Dongkyu
authors: D
authors: Kim
authors: Jung-Yun
authors: JY
authors: Choi
authors: Ilkyun
authors: I
authors: Im
authors: Kyu-Seok
authors: KS
authors: Hwang
authors: Cheol-Hee
authors: CH
authors: Kim
authors: Beom Hee
authors: BH
authors: Lee
authors: Han-Wook
authors: HW
authors: Yoo
authors: Yong-Mahn
authors: YM
authors: Han
mesh_terms: D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D004476:Ectodermal Dysplasia / Q000378:metabolism* / Q000473:pathology*; D058732:Embryoid Bodies / Q000378:metabolism; D019066:Facies; D005183:Failure to Thrive / Q000378:metabolism* / Q000473:pathology*; D006330:Heart Defects, Congenital / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000473:pathology; D021381:Protein Transport; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051785:Smad Proteins; D051176:beta Catenin
keywords: CFC syndrome; ERK signaling; SMAD1 signaling; iPSCs; β-Catenin