Abstract
SummaryThe core planar polarity pathway coordinates epithelial cell polarity during animal development, and loss of its activity gives rise to a range of defects, from aberrant morphogenetic cell movements to failure to correctly orient structures, such as hairs and cilia. The core pathway functions via a mechanism involving segregation of its protein components to opposite cells ends, where they form asymmetric intracellular complexes that couple cell-cell polarity. This segregation is a self-organizing process driven by feedback interactions between the core proteins themselves. Despite intense efforts, the molecular pathways underlying feedback have proven difficult to elucidate using conventional genetic approaches. Here we investigate core protein function during planar polarization of the Drosophila wing by combining quantitative measurements of protein dynamics with loss-of-function genetics, mosaic analysis, and temporal control of gene expression. Focusing on the key core protein Frizzled, we show that its stable junctional localization is promoted by the core proteins Strabismus, Dishevelled, Prickle, and Diego. In particular, we show that the stabilizing function of Prickle on Frizzled requires Prickle activity in neighboring cells. Conversely, Prickle in the same cell has a destabilizing effect on Frizzled. This destabilizing activity is dependent on the presence of Dishevelled and blocked in the absence of Dynamin and Rab5 activity, suggesting an endocytic mechanism. Overall, our approach reveals for the first time essential in vivo stabilizing and destabilizing interactions of the core proteins required for self-organization of planar polarity.
Highlights
Planar polarization describes the property whereby cells show coordinated polarized behaviors within the plane of a tissue and underlies diverse phenomena, including hairs, bristles, and cilia adopting a common orientation on the surface of an epithelium, and groups of cells or neurons showing coordinated directional migrations [1, 2]
Based primarily on studies in the developing Drosophila wing, it has been found that the core pathway proteins have the ability to assemble into asymmetric intercellular junctional complexes formed around a backbone of an intercellular homodimer of the cadherin Flamingo (Fmi; known as Starry Night) associated on one side of the junction with the seven-pass transmembrane protein Frizzled (Fz)
The other components are the four-pass transmembrane protein Strabismus (Stbm; known as Van Gogh), which associates with Fmi on the opposite side of the junction to Fz, the cytoplasmic proteins Dishevelled (Dsh) and Diego (Dgo) that colocalize with Fz, and the cytoplasmic protein Prickle (Pk) that colocalizes with Stbm [4]
Summary
Planar polarization describes the property whereby cells show coordinated polarized behaviors within the plane of a tissue and underlies diverse phenomena, including hairs, bristles, and cilia adopting a common orientation on the surface of an epithelium, and groups of cells or neurons showing coordinated directional migrations [1, 2]. Whereas Fmi and Fz appear to associate stoichiometrically in a 2:1 ratio, the other components of the complex show variable stoichiometries, suggesting a ‘‘signalosome-like’’ organization (Figure 1A) [5]. Such an organization might serve to provide complexes with intrinsic stability, as a result of weak multivalent interactions between complex components driving a phase transition into a stable state [6]
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