Regulation of planar cell polarity by the Dachsous-Fat pathway

Planar cell polarity is the polarization of cells within the plane of a tissue. The Dachsous-Fat pathway plays a key role in the regulation of planar cell polarity and growth during the development of an organism. The transmembrane cadherins Fat and Dachsous from neighboring cells interact heterophilically and regulate the localization of the unconventional myosin Dachs in a cell. Four-jointed, a Golgi-localized kinase modulates the binding between Dachsous and Fat. Dachsous and Four-jointed are expressed in tissue-wide gradients, which influence Fat activity and direct the polarized membrane localization of Dachs. We demonstrate that differential expression of Dachsous or Four-jointed can modulate Dachs polarization at a distance in wing discs. This indicates that Dachsous and Four-jointed gradients can be measured over long range in a tissue through propagation of polarity. We also show that Dachsous and Fat are partially polarized along the endogenous Dachsous and Four-jointed gradients, providing a mechanism for propagation of polarity. Through directed membrane targeting of Dachs, we show that membrane localization of Dachs influences both planar cell polarity and the Hippo signaling pathway. These studies help in understanding the mechanisms involved in establishment and maintenance of planar cell polarity. The Frizzled pathway is another key pathway that regulates planar cell polarity, but its relationship with the Dachsous-Fat pathway was unclear. We demonstrate that Dachs and Dachsous can independently interact with a Frizzled pathway component, Spiny-legs, and direct its localization in vivo. Thus, the Dachsous-Fat pathway provides directional input to the Frizzled pathway by influencing the localization of Spiny-legs. These studies help in understanding how planar cell polarity is regulated in various tissues through coordination between Dachsous-Fat and Frizzled pathways. These studies also reveal that Spiny-legs and its isoform Prickle can respond to distinct planar cell polarity signals and allow the cells to compare and choose between these competing signals to direct polarity robustly in one direction. Thus, our results identify a mechanism for propagation of planar cell polarity through the tissue, establish the significance of Dachs membrane localization in Dachsous-Fat signaling and identify a molecular mechanism for crosstalk between the two planar cell polarity pathways.Ph.D.Includes bibliographical referencesby Abhijit Ashok Ambegaonka