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Science 333 (6040): 342-345

Copyright © 2011 by the American Association for the Advancement of Science

Control of Mitotic Spindle Angle by the RAS-Regulated ERK1/2 Pathway Determines Lung Tube Shape

Nan Tang,1 Wallace F. Marshall,2 Martin McMahon,3 Ross J. Metzger,1,*,{dagger} Gail R. Martin1,*,{dagger}

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.

1 Department of Anatomy, University of California, San Francisco, CA 94158, USA.
2 Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA.
3 Cancer Research Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: ross.metzger{at} (R.J.M.); gail.r.martin{at} (G.R.M.)

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