The Wnt co-receptor Arrow-LRP5/6 is required for planar cell polarity establishment in Drosophila

Wnt-signaling, via β−catenin or the planar cell polarity (PCP) branch, is crucial for development, tissue homeostasis, and linked to many diseases. LRP5/6, arrow/arr in Drosophila, is the obligate co-receptor in Wnt/β−catenin signaling, with ligand binding to a Frizzled (Fz) family member and LRP5/6. Current models for Wnt/PCP signaling omit Arr-LRP5/6 and PCP is presumed functioning without these co-receptors. Here we show that arr-LRP5/6 is fully required in Wnt/PCP signaling. In Drosophila, loss of arr results in aberrant PCP mediated cellular orientation and loss of polarity coordination in wings, comparable to core PCP factors mutations, with defects manifest as loss of asymmetric PCP factor localization and reduced levels of Dishevelled (Dsh) with centrally forming wing hairs. In the eye, arr mutant tissue displays phenotypes with defects in chirality and photoreceptors R3 and R4 cell fates. Functional interactions indicate that Fz can recruit Arr, and Arr potentiates Fz-Dsh PCP signaling in all tissues tested. Furthermore, arr-LRP5/6 sensitizes the ligand pair Wg, Wnt4 with the receptor fz, and the core PCP factors fmi and Vang/stbm to cause PCP defects in heterozygous conditions. Our data support a core PCP function of Arr-LRP5/6, promoting Wnt/Fz-Dsh PCP-complex activity. The LRP5/6 Wnt co-receptor was thought to be specific to Wnt/β-catenin signaling. Our work in Drosophila shows that it is equally critical in Wnt/planar cell polarity signaling, also promoting activity of the common downstream effector Dishevelled.