Enhanced SMAD1 Signaling Contributes to Impairments of Early Development in CFC‐iPSCs

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 p...

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Published in:Stem cells (Dayton, Ohio) Ohio), 2015-05, Vol.33 (5), p.1447-1455
Main Authors: Han, Kyu‐Min, Kim, Seung‐Kyoon, Kim, Dongkyu, Choi, Jung‐Yun, Im, Ilkyun, Hwang, Kyu‐Seok, Kim, Cheol‐Hee, Lee, Beom Hee, Yoo, Han‐Wook, Han, Yong‐Mahn
Format: Article
Language:English
Subjects:
beta Catenin - metabolism
Cell Differentiation
Cell Nucleus - metabolism
CFC syndrome
Defects
Ectodermal Dysplasia - metabolism
Ectodermal Dysplasia - pathology
Embryoid Bodies - metabolism
ERK signaling
Facies
Failure to Thrive - metabolism
Failure to Thrive - pathology
Heart Defects, Congenital - metabolism
Heart Defects, Congenital - pathology
Humans
Induced Pluripotent Stem Cells - metabolism
iPSCs
Male
Neurons - pathology
Protein Transport
Signal Transduction
Smad Proteins - metabolism
SMAD1 signaling
Stem cells
β‐Catenin
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Summary: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. Stem Cells 2015;33:1447–1455
ISSN:1066-5099
1549-4918
DOI:10.1002/stem.1963