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.
Highlights
Recent studies have implicated the planar cell polarity (PCP) genes VANGL1 and VANGL2 in breast cancer[1]
Cells isolated from mammary glands harvested from adult wildtype (WT) mice were FACS purified into three subpopulations: basal (Lin-CD24+CD29hi), mature luminal (Lin-CD24loCD29+CD61−), and luminal progenitor (Lin-CD24loCD29+CD61+)
We address non-canonical WNT/Planar cell polarity (PCP) signaling by directly examining the consequences of aberrant Van Gogh Like (VANGL) receptor function
Summary
Recent studies have implicated the planar cell polarity (PCP) genes VANGL1 and VANGL2 in breast cancer[1]. By E11.5, FGF and WNT signals drive cell fate specification in order to produce the first mammary epithelium[4]. This group of cells further expands around E15.5 to form a mammary bud. We report that Vangl[2] missense and loss-of-function mutations stunt mammary gland development whereas a Vangl[1] hypomorphic mutation does not affect mammary outgrowth or branching morphogenesis. Our studies provide insight into mechanisms that control growth and development in the mammary gland and show a novel mechanism for PCP signaling in influencing transcriptional repressors. Our studies further broaden the scope of non-canonical WNT signaling in the mammary gland and draw useful comparisons between different Vangl loss-of-function models
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