Huntingtin Is Required for Epithelial Polarity through RAB11A-Mediated Apical Trafficking of PAR3-aPKC.
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.
Institut Curie, Orsay, France; CNRS UMR 3306, Orsay, France; INSERM U1005, Orsay, France.
Salah
S
Elias
Institut Curie, Orsay, France; CNRS UMR 3306, Orsay, France; INSERM U1005, Orsay, France.
John Russel
JR
McGuire
Institut Curie, Orsay, France; CNRS UMR 3306, Orsay, France; INSERM U1005, Orsay, France.
Hua
H
Yu
Institut Curie, Orsay, France; CNRS UMR 3306, Orsay, France; INSERM U1005, Orsay, France; Grenoble Institut des Neurosciences, University Grenoble Alpes, Grenoble, France; INSERM U836, Grenoble, France.
Sandrine
S
Humbert
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D018797:Cell Cycle Proteins; D004285:Dogs; D004848:Epithelium / Q000196:embryology*; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D061985:Madin Darby Canine Kidney Cells; D008321:Mammary Glands, Animal / Q000196:embryology; D051379:Mice; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011247:Pregnancy; D011493:Protein Kinase C / Q000378:metabolism*; D022161:Transport Vesicles / Q000502:physiology*; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011493:Protein Kinase C; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C506812:Htt protein, mouse; C115084:Pard3 protein, mouse; C115015:PKC-3 protein