Department of Biological Sciences and Center for Stem Cell Differentiation, KAIST, Daejeon, Republic of Korea.
Stem Cells. 2015 May;33(5):1447-55. doi: 10.1002/stem.1963.
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.
心脏面部皮肤（CFC）综合征是一种由 ERK 信号持续激活引起的发育障碍，主要由 BRAF 突变引起。关于 ERK 信号在 CFC 综合征早期发育中的作用知之甚少。在这里，我们表明 SMAD1 和 ERK 信号通路都可能导致 CFC 综合征的发育缺陷。源自 CFC 综合征患者皮肤成纤维细胞的诱导多能干细胞（iPSCs）显示出类胚体（EB）发育、β-catenin 定位和神经元分化的早期发育缺陷。在 EB 形成过程中，CFC-iPSCs 中的 SMAD1 和 ERK 信号均显著激活。在 CFC-EBs 中，大部分β-catenin与膜分离，并优先定位到核内。此外，SMAD1 信号的激活再现了野生型 iPSCs 的早期发育缺陷。有趣的是，抑制 CFC-iPSCs 中的 SMAD1 信号可挽救异常的 EB 形态、受损的神经元分化和改变的β-catenin 定位。这些结果表明，SMAD1 信号可能是 CFC 综合征在早期发育中导致发病机制的关键途径。
