Crumbs3-Mediated Polarity Directs Airway Epithelial Cell Fate through the Hippo Pathway Effector Yap

• DOI: 10.1016/j.devcel.2015.06.020
• Publication Date: 2015-07-30T16:08:05Z
• Authors: Aleksander D. Szy...; John E. Mahoney; Wellington V. Car...; Xaralabos Varelas
• Keywords: Mice, Knockout; 0303 health sciences; Membrane Glycoproteins; Stem Cells; Intracellular Signaling Peptides and Proteins; Cell Polarity; Membrane Proteins; Cell Cycle Proteins; Cell Differentiation; Epithelial Cells; Respiratory Mucosa; Protein Serine-Threonine Kinases; Phosphoproteins; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Animals; RNA Interference; Phosphorylation; RNA, Small Interfering; Lung; Developmental Biology; Adaptor Proteins, Signal Transducing

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.