[en] Cell polarity is essential for the architecture and function of numerous epithelial tissues. Here, we show that apical restriction of planar cell polarity (PCP) components is necessary for the maintenance of epithelial integrity. Using the mammalian pancreas as a model, we find that components of the core PCP pathway, such as the transmembrane protein Van Gogh-like (VANGL), become apically restricted over a period of several days. Expansion of VANGL localization to the basolateral membranes of progenitors leads to their death and disruption of the epithelial integrity. VANGL basolateral expansion does not affect apico-basal polarity but acts in the cells where Vangl is mislocalized by reducing Dishevelled and its downstream target ROCK. This reduction in ROCK activity culminates in progenitor cell egression, death, and eventually pancreatic hypoplasia. Thus, precise spatiotemporal modulation of VANGL-dependent PCP signaling is crucial for proper pancreatic morphogenesis.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Flasse, Lydie ; Université de Liège - ULiège > GIGA > GIGA Stem Cells - Zebrafish Development and Disease Model ; The Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark, Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany. Electronic address: flasse@mpi-cbg.de
Yennek, Siham; The Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Cortijo, Cédric; Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausannne, Switzerland
Barandiaran, Irene Seijo; Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
Kraus, Marine R-C; Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausannne, Switzerland
Grapin-Botton, Anne; The Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark, Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany. Electronic address: botton@mpi-cbg.de
Language :
English
Title :
Apical Restriction of the Planar Cell Polarity Component VANGL in Pancreatic Ducts Is Required to Maintain Epithelial Integrity.
NNF - Novo Nordisk Fonden EPLF - École Polytechnique Fédérale de Lausanne
Funding text :
We would like to thank M. Figueiredo-Larsen for his experimental contributions with respect to whole-pancreas organoids and Heike Petzold for technical support. We thank D. Devenport for the Cherry-Vangl2 construct and N. Thompson and the EPFL Transgenesis Core Facility for generating the transgenic lines. We are grateful to J. Bulkescher and G. Karemore for their expert assistance with imaging and statistics, respectively, and to J. Brickman and P. Seymour for their comments on the manuscript. We also thank T. Ohtsuka and J. Nathans for the PK2 and Frizzled3 antibodies, respectively. The Novo Nordisk Foundation Center for Stem Cell Biology is supported by Novo Nordisk Foundation grant number NNF17CC0027852 .We would like to thank M. Figueiredo-Larsen for his experimental contributions with respect to whole-pancreas organoids and Heike Petzold for technical support. We thank D. Devenport for the Cherry-Vangl2 construct and N. Thompson and the EPFL Transgenesis Core Facility for generating the transgenic lines. We are grateful to J. Bulkescher and G. Karemore for their expert assistance with imaging and statistics, respectively, and to J. Brickman and P. Seymour for their comments on the manuscript. We also thank T. Ohtsuka and J. Nathans for the PK2 and Frizzled3 antibodies, respectively. The Novo Nordisk Foundation Center for Stem Cell Biology is supported by Novo Nordisk Foundation grant number NNF17CC0027852. L.F. contributed to project design as well as most experimental data collection and analyses; S.Y. contributed to all experiments with the ex vivo systems; I.S.B. contributed to the quantification of CAS3+ cells in the Inversin mutant and in the neural tube and participated in the analysis of the pancreatosphere videos; C.C. characterized hypoplasia in E16.5 Cherry-Vangl2 pancreata; M.R.-C.K. quantified pancreatic size in E14.5 Inversin mutants; C.C. M.R.-C.K. and L.F. demonstrated VANGL upregulation in Inversin mice. A.G.-B. supervised and helped design the project. C.C. is an employee of Neurimmune. M.R-C.K. is an employee of Société des produits Nestlé SA.
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