title: Control of mitotic spindle angle by the RAS-regulated ERK1/2 pathway determines lung tube shape.
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.
authors.affiliation: Department of Anatomy, University of California, San Francisco, CA 94158, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Tang
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA.
authors.forename: Wallace F
authors.initials: WF
authors.lastname: Marshall
authors.affiliation: Cancer Research Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
authors.affiliation: Department of Anatomy, University of California, San Francisco, CA 94158, USA.
authors.forename: Ross J
authors.initials: RJ
authors.lastname: Metzger
authors.affiliation: Department of Anatomy, University of California, San Francisco, CA 94158, USA.
authors.forename: Gail R
authors.initials: GR
authors.lastname: Martin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016764:Cell Polarity; D049109:Cell Proliferation; D048430:Cell Shape; D048429:Cell Size; D004847:Epithelial Cells / Q000166:cytology; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008938:Mitosis; D008954:Models, Biological; D009024:Morphogenesis; D009154:Mutation; D038081:Organogenesis; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000196:embryology*; D008941:Spindle Apparatus / Q000502:physiology* / Q000648:ultrastructure
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; C425468:Spry1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)