The hippo pathway effector Yap controls patterning and differentiation of airway epithelial progenitors

Dev Cell. 2014 Jul 28;30(2):137-50. doi: 10.1016/j.devcel.2014.06.003. Epub 2014 Jul 17.

Abstract

How epithelial progenitor cells integrate local signals to balance expansion with differentiation during organogenesis is still little understood. Here, we provide evidence that the Hippo pathway effector Yap is a key regulator of this process in the developing lung. We show that when epithelial tubules are forming and branching, a nucleocytoplasmic shift in Yap localization marks the boundary between the airway and the distal lung compartments. At this transition zone, Yap specifies a transcriptional program that controls Sox2 expression and ultimately generates the airway epithelium. Without Yap, epithelial progenitors are unable to properly respond to local TGF-β-induced cues and control levels and distribution of Sox2 to form airways. Yap levels and subcellular localization also markedly influence Sox2 expression and differentiation of adult airway progenitors. Our data reveal a role for the Hippo-Yap pathway in integrating growth-factor-induced cues in the developing and adult lung potentially key for homeostasis and regeneration repair.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Body Patterning*
  • Cell Cycle Proteins
  • Cell Differentiation*
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / metabolism
  • Epithelial Cells / cytology*
  • Epithelial Cells / metabolism
  • Gene Expression Regulation, Developmental
  • Lung / cytology*
  • Lung / embryology
  • Lung / metabolism
  • Mice
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism
  • Transcription, Genetic
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Phosphoproteins
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse
  • Transforming Growth Factor beta
  • Yap protein, mouse
  • Hippo protein, mouse
  • Protein-Serine-Threonine Kinases