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标题：VANGL2 regulates luminal epithelial organization and cell turnover in the mammary gland
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作者：Prestina Smith ; Nathan Godde ; Stefany Rubio 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2019
卷号：9
期号：1
页码：1-13
DOI：10.1038/s41598-019-43444-8
出版社：Springer Nature
摘要：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.