title: Crumbs3-Mediated Polarity Directs Airway Epithelial Cell Fate through the Hippo Pathway Effector Yap.
abstract: Epithelial cells undergo dynamic polarity changes as organs pattern, but the relationship between epithelial polarity and cell fate is poorly understood. Using the developing lung as a model, we found that distinct alterations in apical-basal polarity dictate airway epithelial differentiation. We demonstrate that Crb3, a Crumbs isoform that determines epithelial apical domain identity, is required for airway differentiation by controlling the localization of the transcriptional regulator Yap. We show that Crb3 promotes the interaction between Yap and the Hippo pathway kinases Lats1/2 at apical cell junctions to induce Yap phosphorylation and cytoplasmic retention, which drive cell differentiation. Loss of Crb3 in developing mouse airways or isolated adult airway progenitors results in unrestricted nuclear Yap activity and consequent cell differentiation defects. Our findings demonstrate that polarity-dependent cues control airway cell differentiation, offering important molecular insights into organ patterning.
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Aleksander D
authors.initials: AD
authors.lastname: Szymaniak
authors.affiliation: Department of Pathology, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Mahoney
authors.affiliation: Department of Pathology, Boston University School of Medicine, Boston, MA 02118, USA; Columbia Center for Human Development, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Wellington V
authors.initials: WV
authors.lastname: Cardoso
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address: xvarelas@bu.edu.
authors.forename: Xaralabos
authors.initials: X
authors.lastname: Varelas
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000235:genetics; D016764:Cell Polarity; D004847:Epithelial Cells / Q000166:cytology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008168:Lung / Q000196:embryology; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D020545:Respiratory Mucosa / Q000166:cytology; D013234:Stem Cells / Q000166:cytology; D015534:Trans-Activators / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C530695:Crb3 protein, mouse; C486419:Trp63 protein, mouse; C486223:Yap1 protein, mouse; C508433:scrib protein, mouse; C490501:Lats1 protein, mouse; C522633:LATS2 protein, mouse