Hippo signaling promotes lung epithelial lineage commitment by curbing Fgf10 and β-catenin signaling

Development. 2019 Jan 16;146(2):dev166454. doi: 10.1242/dev.166454.

Abstract

Organ growth and tissue homeostasis rely on the proliferation and differentiation of progenitor cell populations. In the developing lung, localized Fgf10 expression maintains distal Sox9-expressing epithelial progenitors and promotes basal cell differentiation in the cartilaginous airways. Mesenchymal Fgf10 expression is induced by Wnt signaling but inhibited by Shh signaling, and epithelial Fgf10 signaling activates β-catenin signaling. The Hippo pathway is a well-conserved signaling cascade that regulates organ size and stem/progenitor cell behavior. Here, we show that Hippo signaling promotes lineage commitment of lung epithelial progenitors by curbing Fgf10 and β-catenin signaling. Our findings show that both inactivation of the Hippo pathway (nuclear Yap) or ablation of Yap result in increased β-catenin and Fgf10 signaling, suggesting a cytoplasmic role for Yap in epithelial lineage commitment. We further demonstrate redundant and non-redundant functions for the two nuclear effectors of the Hippo pathway, Yap and Taz, during lung development.

Keywords: Differentiation; Fgf10; Fgfr2; Hippo; Ilk; Integrin; Lung; Progenitor; Yap; β-Catenin.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Cycle Proteins
  • Cell Differentiation
  • Cell Lineage*
  • Cytoplasm / metabolism
  • Epithelial Cells / cytology*
  • Epithelial Cells / metabolism*
  • Female
  • Fibroblast Growth Factor 10 / metabolism*
  • Lung / cytology*
  • Lung / embryology
  • Male
  • Mice
  • Models, Biological
  • Organogenesis
  • Phenotype
  • Phosphoproteins / metabolism
  • Protein-Serine-Threonine Kinases / metabolism*
  • Pulmonary Alveoli / embryology
  • Signal Transduction*
  • beta Catenin / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Fgf10 protein, mouse
  • Fibroblast Growth Factor 10
  • Phosphoproteins
  • Wwtr1 protein, mouse
  • Yap protein, mouse
  • beta Catenin
  • integrin-linked kinase
  • Hippo protein, mouse
  • Protein-Serine-Threonine Kinases