title: Collective polarization model for gradient sensing via Dachsous-Fat intercellular signaling.
abstract: Dachsous-Fat signaling via the Hippo pathway influences proliferation during Drosophila development, and some of its mammalian homologs are tumor suppressors, highlighting its role as a universal growth regulator. The Fat/Hippo pathway responds to morphogen gradients and influences the in-plane polarization of cells and orientation of divisions, linking growth with tissue patterning. Remarkably, the Fat pathway transduces a growth signal through the polarization of transmembrane complexes that responds to both morphogen level and gradient. Dissection of these complex phenotypes requires a quantitative model that provides a systematic characterization of the pathway. In the absence of detailed knowledge of molecular interactions, we take a phenomenological approach that considers a broad class of simple models, which are sufficiently constrained by observations to enable insight into possible mechanisms. We predict two modes of local/cooperative interactions among Fat-Dachsous complexes, which are necessary for the collective polarization of tissues and enhanced sensitivity to weak gradients. Collective polarization convolves level and gradient of input signals, reproducing known phenotypes while generating falsifiable predictions. Our construction of a simplified signal transduction map allows a generalization of the positional value model and emphasizes the important role intercellular interactions play in growth and patterning of tissues.
authors.affiliation: Kavli Institute for Theoretical Physics and Department of Physics, University of California, Santa Barbara, CA 93101.
authors.forename: Madhav
authors.initials: M
authors.lastname: Mani
authors.forename: Sidhartha
authors.initials: S
authors.lastname: Goyal
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Irvine
authors.forename: Boris I
authors.initials: BI
authors.lastname: Shraiman
mesh_terms: D000818:Animals; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008954:Models, Biological; D009024:Morphogenesis / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000099317:Hippo Kinases
chemical_list: D000070585:Cadherin Related Proteins; D015820:Cadherins; D015815:Cell Adhesion Molecules; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; C442479:DCHS1 protein, human; C472307:ft protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases
keywords: cell–cell signaling; modelling; morphogenesis