Abstract
The establishment of apical-basolateral polarity is important for both normal development and disease, for example, during tumorigenesis and metastasis. During this process, polarity complexes are targeted to the apical surface by a RAB11A-dependent mechanism. Huntingtin (HTT), the protein that is mutated in Huntington disease, acts as a scaffold for molecular motors and promotes microtubule-based dynamics. Here, we investigated the role of HTT in apical polarity during the morphogenesis of the mouse mammary epithelium. We found that the depletion of HTT from luminal cells in vivo alters mouse ductal morphogenesis and lumen formation. HTT is required for the apical localization of PAR3-aPKC during epithelial morphogenesis in virgin, pregnant, and lactating mice. We show that HTT forms a complex with PAR3, aPKC, and RAB11A and ensures the microtubule-dependent apical vesicular translocation of PAR3-aPKC through RAB11A. We thus propose that HTT regulates polarized vesicular transport, lumen formation and mammary epithelial morphogenesis.
Highlights
Epithelial cells in glandular and tubular epithelial systems are organized as one layer surrounding a lumen
In the adult mammary gland, tissue architecture is maintained through the regulation of the polarity of epithelial cells, which organize around a central cavity called the lumen
The protein complex composed of PAR3, PAR6, and atypical protein kinase C (aPKC) regulates apical polarity in several tissues, including the mammary epithelium, and it is known that the loss of PAR3 and aPKC interferes with mammary gland development and promotes mammary tumor metastasis
Summary
Epithelial cells in glandular and tubular epithelial systems are organized as one layer surrounding a lumen. The establishment of apical-basolateral polarity in these systems is characterized by the formation of cell–cell adherens and tight junctions and accompanies lumen formation (reviewed in [1,2,3]). This organization provides a functional barrier that regulates the polarized secretion and intake of molecules. The Crumbs (CRB) complex, which is required to establish the apical membrane, is composed of the transmembrane protein CRB and the associated cytoplasmic proteins, PALS1 ( known as MPP5) and PALS1-associated tight junction protein (PATJ; known as INADL). In Drosophila, these complexes interact and establish the apical and basolateral surfaces of epithelial cells by a system of mutual exclusion [5,6]
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