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Sci Rep. 2019 May 8;9(1):7079. doi: 10.1038/s41598-019-43444-8.

VANGL2 regulates luminal epithelial organization and cell turnover in the mammary gland.

Author information

1
Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA, 95064, USA.
2
Cell Cycle and Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, St Andrews Place, Melbourne, VIC, 3002, Australia.
3
Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, 3010, Australia.
4
Australian Animal Health Laboratory, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Victoria, 3220, Australia.
5
Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
6
Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine and Department of Cell and Developmental Biology, University of Colorado Denver School of Medicine, Aurora, CO, 80045, USA.
7
Cardiovascular Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
8
Department of Biochemistry & Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.
9
Department of Biochemistry & Genetics, University of Melbourne, Parkville, VIC, 3010, Australia.
10
Department of Clinical Pathology, University of Melbourne, Parkville, VIC, 3010, Australia.
11
Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA, 95064, USA. lhinck@ucsc.edu.

Abstract

The VANGL family of planar cell polarity proteins is implicated in breast cancer however its function in mammary gland biology is unknown. Here, we utilized a panel of Vang1 and Vangl2 mouse alleles to examine the requirement of VANGL family members in the murine mammary gland. We show that Vang1CKOΔ/Δ glands display normal branching while Vangl2flox/flox and Vangl2Lp/Lp tissue exhibit several phenotypes. In MMTV-Cre;Vangl2flox/flox glands, cell turnover is reduced and lumens are narrowed. A Vangl2 missense mutation in the Vangl2Lp/Lp tissue leads to mammary anlage sprouting defects and deficient outgrowth with transplantation of anlage or secondary tissue fragments. In successful Vangl2Lp/Lp outgrowths, three morphological phenotypes are observed: distended ducts, supernumerary end buds, and ectopic acini. Layer specific defects are observed with loss of Vangl2 selectively in either basal or luminal layers of mammary cysts. Loss in the basal compartment inhibits cyst formation, but has the opposite effect in the luminal compartment. Candidate gene analysis on MMTV-Cre;Vangl2flox/flox and Vangl2Lp/Lp tissue reveals a significant reduction in Bmi1 expression, with overexpression of Bmi1 rescuing defects in Vangl2 knockdown cysts. Our results demonstrate that VANGL2 is necessary for normal mammary gland development and indicate differential functional requirements in basal versus luminal mammary compartments.

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