Nuclear VANGL2 Inhibits Lactogenic Differentiation.

Planar cell polarity (PCP) proteins coordinate tissue morphogenesis by governing cell patterning and polarity. Asymmetrically localized on the plasma membrane of cells, PCP proteins are also trafficked by endocytosis, suggesting they may have intracellular functions that are dependent or independent of their extracellular role, but whether these functions extend to transcriptional control remains unknown. Here, we show the nuclear localization of transmembrane, PCP protein, VANGL2, in undifferentiated, but not differentiated, HC11 cells, which serve as a model for mammary lactogenic differentiation. Loss of function results in upregulation of pathways related to STAT5 signaling. We identify DNA binding sites and a nuclear localization signal in VANGL2, and use CUT&RUN to demonstrate direct binding of VANGL2 to specific DNA binding motifs, including one in the promoter. Knockdown (KD) of in HC11 cells and primary mammary organoids results in upregulation of , and , larger acini and organoids, and precocious differentiation; phenotypes rescued by overexpression of , but not . Together, these results advance a paradigm whereby PCP proteins coordinate tissue morphogenesis by keeping transcriptional programs governing differentiation in check.