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The Hospital for Sick Children, University of Toronto

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Dev. Cell, Volume 52, Issue 5, 9 March 2020, Pages 647-658.e6 | https://doi.org/10.1016/j.devcel.2020.02.003 Hedgehog-Activated Fat4 and PCP Pathways Mediate Mesenchymal Cell Clustering and Villus Formation in Gut Development

Abilasha Rao-Bhatia^1,2, Min Zhu^1,3, Wen-ChiYin^1,2, Sabrina Coquenlorge^1,2, Xiaoyun Zhang^1,2, Janghee Woo^4,5, Yu Sun³, Charlotte H. Dean⁶, Aimin Liu⁷, Chi-chung Hui^1,2, Ramesh A. Shivdasani^4,5, Helen McNeill^2,8, Sevan Hopyan^1,2, Tae-Hee Kim^1,2,9,*

¹Program in Developmental & Stem Cell Biology, the Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
²Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
³Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON M5S 3G8, Canada
⁴Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
⁵Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
⁶Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College London, London, UK
⁷Department of Biology, Eberly College of Science, Centers for Cellular Dynamics and Molecular Investigation of Neurological Disorders, Huck Institute of Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA
⁸Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA
⁹Lead Contact

^*Corresponding author

Abstract

During development, intestinal epithelia undergo dramatic morphogenesis mediated by mesenchymal signaling to form villi, which are required for efficient nutrient absorption and host defense. Although both smooth-muscle-induced physical forces and mesenchymal cell clustering beneath emerging villi are implicated in epithelial folding, the underlying cellular mechanisms are unclear. Hedgehog (Hh) signaling can mediate both processes. We therefore analyzed its direct targetome and revealed GLI2 transcriptional activation of atypical cadherin and planar cell polarity (PCP) genes. By examining Fat4 and Dchs1 knockout mice, we demonstrate their critical roles in villus formation. Analyses of PCP-mutant mice and genetic interaction studies show that the Fat4-Dchs1 axis acts in parallel to the core-Vangl2 PCP axis to control mesenchymal cell clustering. Moreover, live light-sheet fluorescence microscopy and cultured PDGFRα+ cells reveal a requirement for PCP in their oriented cell migration guided by WNT5A. Therefore, mesenchymal PCP induced by Hh signaling drives cell clustering and subsequent epithelial remodeling.

논문정보

형식Research article
게재일2020년 03월 (BRIC 등록일 2021-01-11)
연구진국외 연구진
분야 생명과학 > 분자생물학
구분구・추천논문

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