Regulation of Hippo signaling and planar cell polarity via distinct regions of the Fat intracellular domain.

The large Drosophila protocadherin Fat (Ft) is a receptor for signal transduction pathways that control growth (Hippo signaling), planar cell polarity (PCP), metabolism and the proximodistal patterning of appendages. The intracellular domain (ICD) of Ft is crucial in implementing its biological functions. Six regions of high conservation (named A-F) within the ICD have been identified, as well as distinct regions mediating Hippo pathway activity that have been functionally characterized via transgenic expression rescue assays. Here, we make targeted deletions of these highly conserved residues and the putative Hippo- and PCP-regulating domains of endogenous Ft using CRISPR/Cas9. Through transcriptomic, developmental and phenotypic analyses, we show that different regions of Ft contribute uniquely to chromatin dynamics, tissue morphogenesis, PCP and metabolic regulation. We also demonstrate that different regions of Ft regulate growth in opposite directions, with regions B and F promoting growth and region D inhibiting growth. Strikingly, conserved regions D and F are key regulators of the function of Ft in Hippo activity - exhibiting opposing effects on Hippo pathway modulation - and of the conserved regions, and D is the main regulator of PCP.