Paxillin-dependent regulation of apical-basal polarity in mammary gland morphogenesis

• Published in: Development (Cambridge) Vol. 146; no. 9
• Main Authors: Xu, Weiyi, Gulvady, Anushree C, Goreczny, Gregory J, Olson, Eric C, Turner, Christopher E
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01.05.2019
• Subjects: Animals; Cell Movement - genetics; Cell Movement - physiology; Cell Polarity - genetics; Cell Polarity - physiology; Epithelial Cells - cytology; Epithelial Cells - metabolism; Extracellular Matrix - metabolism; Mammary Glands, Animal - cytology; Mammary Glands, Animal - metabolism; Mice; Microtubules - metabolism; Morphogenesis - genetics; Morphogenesis - physiology; Paxillin - genetics; Paxillin - metabolism; Signal Transduction - genetics; Signal Transduction - physiology; Cytoskeleton; Extracellular matrix; Cell polarity; Focal adhesions; Vesicle trafficking; Tubulin acetylation
• ISSN: 0950-1991; 1477-9129
• DOI: 10.1242/dev.174367

Establishing apical-basal epithelial cell polarity is fundamental for mammary gland duct morphogenesis during mammalian development. While the focal adhesion adapter protein paxillin is a well-characterized regulator of mesenchymal cell adhesion signaling, F-actin cytoskeleton remodeling and single cell migration, its role in epithelial tissue organization and mammary gland morphogenesis has not been investigated. Here, using a newly developed paxillin conditional knockout mouse model with targeted ablation in the mammary epithelium, in combination with three-dimensional organoid and acini cultures, we identify new roles for paxillin in the establishment of apical-basal epithelial cell polarity and lumen formation, as well as mammary gland duct diameter and branching. Paxillin is shown to be required for the integrity and apical positioning of the Golgi network, Par complex and the Rab11/MyoVb trafficking machinery. Paxillin depletion also resulted in reduced levels of apical acetylated microtubules, and rescue experiments with the HDAC6 inhibitor tubacin highlight the central role for paxillin-dependent regulation of HDAC6 activity and associated microtubule acetylation in controlling epithelial cell apical-basal polarity and tissue branching morphogenesis.