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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Cell Polarity
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Cell Proliferation
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Cell Shape
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Cell Size
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Epithelial Cells / cytology
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Fibroblast Growth Factor 10 / genetics
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Fibroblast Growth Factor 10 / metabolism
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Intracellular Signaling Peptides and Proteins
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Lung / cytology
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Lung / embryology*
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Lung / metabolism
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MAP Kinase Signaling System*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3 / metabolism*
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Mitosis
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Models, Biological
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Morphogenesis*
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Mutation
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Organogenesis
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins p21(ras) / genetics
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Proto-Oncogene Proteins p21(ras) / metabolism*
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Respiratory Mucosa / cytology
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Respiratory Mucosa / embryology*
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Spindle Apparatus / physiology*
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Spindle Apparatus / ultrastructure
Substances
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Adaptor Proteins, Signal Transducing
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Fgf10 protein, mouse
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Fibroblast Growth Factor 10
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Phosphoproteins
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Spry1 protein, mouse
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Protein Serine-Threonine Kinases
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Spry2 protein, mouse
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Hras protein, mouse
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Proto-Oncogene Proteins p21(ras)