RHOA GTPase Controls YAP-Mediated EREG Signaling in Small Intestinal Stem Cell Maintenance
| Autor: | Yi Zheng, Ashley Kuenzi Davis, Yuxin Feng, Kodandaramireddy Nalapareddy, Xuan Zhou, Leesa Sampson, Feng Bi, Zheng Zhang, Hartmut Geiger, Ming Liu, Shailaja Akunuru, Jaime Melendez, Mei Xin |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
rho GTP-Binding Proteins
0301 basic medicine RHOA Cellular differentiation Cell Cycle Proteins Biochemistry Epiregulin Epithelium Mice Intestine Small Morphogenesis lcsh:QH301-705.5 Wnt Signaling Pathway beta Catenin Epithelial polarity Mice Knockout lcsh:R5-920 biology Stem Cells Rho GTPase Wnt signaling pathway Gene Expression Regulation Developmental Cell Differentiation Cell biology Hippo signaling YAP lcsh:Medicine (General) inorganic chemicals Beta-catenin mouse model intestinal stem cell digestive system Article 03 medical and health sciences Genetics Animals Adaptor Proteins Signal Transducing Cell Proliferation Hippo signaling pathway fungi YAP-Signaling Proteins RhoA Cell Biology Phosphoproteins Wnt signaling 030104 developmental biology lcsh:Biology (General) regeneration Cancer research biology.protein rhoA GTP-Binding Protein Developmental Biology |
| Zdroj: | Stem Cell Reports Stem Cell Reports, Vol 9, Iss 6, Pp 1961-1975 (2017) |
| ISSN: | 2213-6711 |
| Popis: | Summary 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 Catnblox(ex3) mutant expression rescues the RhoA KO ISC phenotypes. Thus, RHOA controls YAP-EREG signaling to regulate intestinal homeostasis and ISC regeneration. Highlights • Inducible RHOA deletion in mice causes defects in intestinal structure and polarity • RHOA controls intestinal stem cell proliferation and Hippo signaling • Active YAP/EREG, as well as β-catenin, rescues ISC loss caused by RHOA deficiency • RHOA-YAP-EREG signaling mediates intestinal maintenance and ISC regeneration In this article, Zheng and colleagues show that inducible RHOA deletion in mice causes defects in intestine epithelial polarity and deficiencies in intestinal stem cell proliferation, survival, and regeneration. They further demonstrate by genetic rescues that RHOA controls a YAP-EREG axis to mediate canonical Wnt signaling, intestinal stem cell function, and intestinal homeostasis. |
| Databáze: | OpenAIRE |
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