Division of Experimental Hematology & Cancer Biology, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China.
Division of Experimental Hematology & Cancer Biology, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Stem Cell Reports. 2017 Dec 12;9(6):1961-1975. doi: 10.1016/j.stemcr.2017.10.004. Epub 2017 Nov 9.
RHOA, a founding member of the Rho GTPase family, is critical for actomyosin dynamics, polarity, and morphogenesis in response to developmental cues, mechanical stress, and inflammation. In murine small intestinal epithelium, inducible RHOA deletion causes a loss of epithelial polarity, with disrupted villi and crypt organization. In the intestinal crypts, RHOA deficiency results in reduced cell proliferation, increased apoptosis, and a loss of intestinal stem cells (ISCs) that mimic effects of radiation damage. Mechanistically, RHOA loss reduces YAP signaling of the Hippo pathway and affects YAP effector epiregulin (EREG) expression in the crypts. Expression of an active YAP (S112A) mutant rescues ISC marker expression, ISC regeneration, and ISC-associated Wnt signaling, but not defective epithelial polarity, in RhoA knockout mice, implicating YAP in RHOA-regulated ISC function. EREG treatment or active β-catenin Catnb mutant expression rescues the RhoA KO ISC phenotypes. Thus, RHOA controls YAP-EREG signaling to regulate intestinal homeostasis and ISC regeneration.
RHOA 是 Rho GTPase 家族的创始成员之一，对于肌动球蛋白动力学、极性和形态发生至关重要，以响应发育线索、机械应激和炎症。在小鼠小肠上皮中，诱导型 RHOA 缺失导致上皮极性丧失，绒毛和隐窝组织紊乱。在肠隐窝中，RHOA 缺乏导致细胞增殖减少、细胞凋亡增加和肠干细胞 (ISC) 丢失，这些类似于辐射损伤的效应。在机制上，RHOA 丧失会降低 Hippo 通路的 YAP 信号，并影响隐窝中的 YAP 效应物表皮调节素 (EREG) 的表达。表达活性 YAP（S112A）突变可挽救 RhoA 敲除小鼠中的 ISC 标记物表达、ISC 再生和 ISC 相关的 Wnt 信号，但不能纠正上皮极性缺陷，表明 YAP 参与 RHOA 调节的 ISC 功能。EREG 治疗或活性 β-连环蛋白 Catnb 突变体表达可挽救 RhoA KO ISC 表型。因此，RHOA 控制 YAP-EREG 信号以调节肠道稳态和 ISC 再生。
