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

Dev Cell. 2015 Aug 10;34(3):283-96. doi: 10.1016/j.devcel.2015.06.020. Epub 2015 Jul 30.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Cycle Proteins
  • Cell Differentiation / genetics
  • Cell Polarity*
  • Epithelial Cells / cytology
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lung / embryology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • RNA, Small Interfering
  • Respiratory Mucosa / cytology
  • Stem Cells / cytology
  • Trans-Activators / metabolism
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Crb3 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Phosphoproteins
  • RNA, Small Interfering
  • Trans-Activators
  • Trp63 protein, mouse
  • Tumor Suppressor Proteins
  • Yap protein, mouse
  • scribble protein, mouse
  • Lats1 protein, mouse
  • LATS2 protein, mouse
  • Protein-Serine-Threonine Kinases