The Drosophila Hedgehog receptor component Interference hedgehog (Ihog) mediates cell-cell interactions through trans-homophilic binding.

Hedgehog (Hh) signaling is crucial for establishing complex cellular patterns in embryonic tissues and maintaining homeostasis in adult organs. In Drosophila, Interference hedgehog (Ihog) or its close paralogue Brother of Ihog (Boi) forms a receptor complex with Patched to mediate intracellular Hh signaling. Ihog proteins (Ihog and Boi) also contribute to cell segregation in wing imaginal discs through an unknown mechanism independent of their role in transducing the Hh signal. Here, we report a molecular mechanism by which the Ihog proteins mediate cell-cell interactions. We found that Ihog proteins are enriched at the site of cell-cell contacts and engage in trans-homophilic interactions in a calcium-independent manner. The region that we identified as mediating the trans-Ihog-Ihog interaction overlaps with the Ihog-Hh interface on the first fibronectin repeat of the extracellular domain of Ihog. We further demonstrate that Hh interferes with Ihog-mediated homophilic interactions by competing for Ihog binding. These results, thus, not only reveal a mechanism for Ihog-mediated cell-cell interactions but also suggest a direct Hh-mediated regulation of both intracellular signaling and cell adhesion through Ihog.