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

Lookup NU author(s): Professor Deborah Henderson

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2019, The Author(s). 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 Vang1CKO Δ/Δ glands display normal branching while Vangl2 flox/flox and Vangl2 Lp/Lp tissue exhibit several phenotypes. In MMTV-Cre;Vangl2 flox/flox glands, cell turnover is reduced and lumens are narrowed. A Vangl2 missense mutation in the Vangl2 Lp/Lp tissue leads to mammary anlage sprouting defects and deficient outgrowth with transplantation of anlage or secondary tissue fragments. In successful Vangl2 Lp/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;Vangl2 flox/flox and Vangl2 Lp/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.


Publication metadata

Author(s): Smith P, Godde N, Rubio S, Tekeste M, Vladar EK, Axelrod JD, Henderson DJ, Milgrom-Hoffman M, Humbert PO, Hinck L

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2019

Volume: 9

Issue: 1

Online publication date: 08/05/2019

Acceptance date: 06/12/2018

ISSN (electronic): 2045-2322

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41598-019-43444-8

DOI: 10.1038/s41598-019-43444-8

PubMed id: 31068622


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