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

ABSTRACT: 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.

SUBMITTER: Wu X

PROVIDER: S-EPMC6699836 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Wu Xuefeng X Zhang Ya Y Chuang Kun-Han KH Cai Xudong X Ajaz Humna H Zheng Xiaoyan X

The Journal of biological chemistry 20190617 33

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 r ...[more]

PMID: 31209108

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Project description:BackgroundThe Hedgehog (Hh) signaling pathway is important for the development of a variety of tissues in both vertebrates and invertebrates. For example, in developing nervous systems Hh signaling is required for the normal differentiation of neural progenitors into mature neurons. The molecular signaling mechanism underlying the function of Hh is not fully understood. In Drosophila, Ihog (Interference hedgehog) and Boi (Brother of Ihog) are related transmembrane proteins of the immunoglobulin superfamily (IgSF) with orthologs in vertebrates. Members of this IgSF subfamily have been shown to bind Hh and promote pathway activation but their exact role in the Hh signaling pathway has remained elusive. To better understand this role in vivo, we generated loss-of-function mutations of the ihog and boi genes, and investigated their effects in developing eye and wing imaginal discs.ResultsWhile mutation of either ihog or boi alone had no discernible effect on imaginal tissues, cells in the developing eye disc that were mutant for both ihog and boi failed to activate the Hh pathway, causing severe disruption of photoreceptor differentiation in the retina. In the anterior compartment of the developing wing disc, where different concentrations of the Hh morphogen elicit distinct cellular responses, cells mutant for both ihog and boi failed to activate responses at either high or low thresholds of Hh signaling. They also lost their affinity for neighboring cells and aberrantly sorted out from the anterior compartment of the wing disc into posterior territory. We found that ihog and boi are required for the accumulation of the essential Hh signaling mediator Smoothened (Smo) in Hh-responsive cells, providing evidence that Ihog and Boi act upstream of Smo in the Hh signaling pathway.ConclusionsThe consequences of boi;ihog mutations for eye development, neural differentiation and wing patterning phenocopy those of smo mutations and uncover an essential role for Ihog and Boi in the Hh signaling pathway.

Dataset Information

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

Publications

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

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