Modelling and Analysis of Planar Cell Polarity

Schamberg, Sabine; Houston, Paul; Monk, Nick; Owen, Markus R.

doi:10.1007/s11538-009-9464-0

Cited by 34 publications

(41 citation statements)

References 23 publications

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“…Although the key molecular plays are very different, the collective polarization model that we have proposed has a similar mechanism of action as previous models of PCP (28,36). In both cases, cooperative and inhibitory interactions make possible spontaneous polarization, which can align across the cell and effectively propagate from a cell to its neighbors.…”

Section: Discussionsupporting

confidence: 53%

Collective polarization model for gradient sensing via Dachsous-Fat intercellular signaling

Mani

Goyal

Irvine

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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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 FatDachsous 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.morphogenesis | cell-cell signaling | modelling

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Section: Discussionsupporting

confidence: 53%

Collective polarization model for gradient sensing via Dachsous-Fat intercellular signaling

Mani

Goyal

Irvine

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Computational modeling has suggested that the cytoplasmic proteins play key roles in promoting feedback interactions between the core proteins (e.g., Amonlirdviman et al., 2005, Le Garrec et al., 2006, Burak and Shraiman, 2009, Schamberg et al., 2010). However, modulating their levels in puncta had no effect on core protein asymmetry (Figures 3O and 3P), indicating that feedback and generation of asymmetry does not depend on an exact ratio or concentration of particular cytoplasmic core proteins at the cell junctions.…”

Section: Resultsmentioning

confidence: 99%

“…However, the core proteins can self-organize: clones of cells lacking Fz activity recruit core proteins to clone boundaries (Usui et al., 1999, Strutt, 2001), resulting in a reversal of polarity on one side of the clone, which can be propagated over several rows of cells (Vinson and Adler, 1987). Moreover, computational models have shown that positive and negative feedback interactions between the core proteins may be sufficient to amplify a slight bias in localization or activity of one of the proteins (e.g., Amonlirdviman et al., 2005, Le Garrec et al., 2006, Burak and Shraiman, 2009, Schamberg et al., 2010). …”

Section: Introductionmentioning

confidence: 99%

Robust Asymmetric Localization of Planar Polarity Proteins Is Associated with Organization into Signalosome-like Domains of Variable Stoichiometry

2016

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SummaryIn developing epithelia, the core planar polarity proteins physically interact with each other and localize asymmetrically at opposite cell ends, forming intercellular complexes that link the polarity of neighboring cells. Using quantitative imaging to examine the composition of the core protein complex in vivo, we find that complex composition is unexpectedly plastic. The transmembrane proteins Frizzled and Flamingo form a stoichiometric nucleus in the complex, while the relative levels of the other four core proteins can vary independently. Exploring the functional consequences of this, we show that robust cell polarization is achieved over a range of complex stoichiometries but is dependent on maintaining appropriate levels of the components Frizzled and Strabismus. We propose that the core proteins assemble into signalosome-like structures, where stable association is not dependent on one-to-one interactions with binding partners, and signaling functions can act over a wide range of complex compositions.

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“…This model further suggested that a directional cue provided by Ft-Ds-Fj system is crucial for explaining the observed PCP patterns [21]; however, it did not elucidate how the Ft-Ds-Fj system as such generates this cue. Further, attempts at mathematical modeling of PCP captured the mechanism of action of the core proteins, and strengthened the idea that a weak tissue-level directional cue is important for obtaining the experimentally observed PCP patterns[23]–[30]. A recent phenomenological model proposes how Ft-Ds heterodimer formation in a group of cells in the tissue can induce collective polarization over the entire tissue; however, this model did not factor the crucial question of the role played by tissue-level expression gradients of Ds and Fj for the regulation of PCP [31].…”

Section: Introductionmentioning

confidence: 93%

Mathematical Modeling of Sub-Cellular Asymmetry of Fat-Dachsous Heterodimer for Generation of Planar Cell Polarity

et al. 2014

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Planar Cell Polarity (PCP) is an evolutionarily conserved characteristic of animal tissues marked by coordinated polarization of cells or structures in the plane of a tissue. In insect wing epithelium, for instance, PCP is characterized by en masse orientation of hairs orthogonal to its apical-basal axis and pointing along the proximal-distal axis of the organ. Directional cue for PCP has been proposed to be generated by complex sets of interactions amongst three proteins - Fat (Ft), Dachsous (Ds) and Four-jointed (Fj). Ft and Ds are two atypical cadherins, which are phosphorylated by Fj, a Golgi kinase. Ft and Ds from adjacent cells bind heterophilically via their tandem cadherin repeats, and their binding affinities are regulated by Fj. Further, in the wing epithelium, sub-cellular levels of Ft-Ds heterodimers are seen to be elevated at the distal edges of individual cells, prefiguring their PCP. Mechanisms generating this sub-cellular asymmetry of Ft-Ds heterodimer in proximal and distal edges of cells, however, have not been resolved yet. Using a mathematical modeling approach, here we provide a framework for generation of this sub-cellular asymmetry of Ft-Ds heterodimer. First, we explain how the known interactions within Ft-Ds-Fj system translate into sub-cellular asymmetry of Ft-Ds heterodimer. Second, we show that this asymmetric localization of Ft-Ds heterodimer is lost when tissue-level gradient of Fj is flattened, or when phosphorylation of Ft by Fj is abolished, but not when tissue-level gradient of Ds is flattened or when phosphorylation of Ds is abrogated. Finally, we show that distal enrichment of Ds also amplifies Ft-Ds asymmetry. These observations reveal that gradient of Fj expression, phosphorylation of Ft by Fj and sub-cellular distal accumulation of Ds are three critical elements required for generating sub-cellular asymmetry of Ft-Ds heterodimer. Our model integrates the known experimental data and presents testable predictions for future studies.

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Modelling and Analysis of Planar Cell Polarity

Cited by 34 publications

References 23 publications

Collective polarization model for gradient sensing via Dachsous-Fat intercellular signaling

Collective polarization model for gradient sensing via Dachsous-Fat intercellular signaling

Robust Asymmetric Localization of Planar Polarity Proteins Is Associated with Organization into Signalosome-like Domains of Variable Stoichiometry

Mathematical Modeling of Sub-Cellular Asymmetry of Fat-Dachsous Heterodimer for Generation of Planar Cell Polarity

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