Control of mitotic spindle angle by the RAS-regulated ERK1/2 pathway determines lung tube shape

Science. 2011 Jul 15;333(6040):342-345. doi: 10.1126/science.1204831.

Abstract

During early lung development, airway tubes change shape. Tube length increases more than circumference as a large proportion of lung epithelial cells divide parallel to the airway longitudinal axis. We show that this bias is lost in mutants with increased extracellular signal-regulated kinase 1 (ERK1) and ERK2 activity, revealing a link between the ERK1/2 signaling pathway and the control of mitotic spindle orientation. Using a mathematical model, we demonstrate that change in airway shape can occur as a function of spindle angle distribution determined by ERK1/2 signaling, independent of effects on cell proliferation or cell size and shape. We identify sprouty genes, which encode negative regulators of fibroblast growth factor 10 (FGF10)-mediated RAS-regulated ERK1/2 signaling, as essential for controlling airway shape change during development through an effect on mitotic spindle orientation.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Cell Polarity
  • Cell Proliferation
  • Cell Shape
  • Cell Size
  • Epithelial Cells / cytology
  • Fibroblast Growth Factor 10 / genetics
  • Fibroblast Growth Factor 10 / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Lung / cytology
  • Lung / embryology*
  • Lung / metabolism
  • MAP Kinase Signaling System*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Mitosis
  • Models, Biological
  • Morphogenesis*
  • Mutation
  • Organogenesis
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / embryology*
  • Spindle Apparatus / physiology*
  • Spindle Apparatus / ultrastructure

Substances

  • Adaptor Proteins, Signal Transducing
  • Fgf10 protein, mouse
  • Fibroblast Growth Factor 10
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Phosphoproteins
  • Spry1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Spry2 protein, mouse
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)