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The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla.

ABSTRACT: Hedgehog (Hh) proteins specify tissue pattern in metazoan embryos by forming gradients that emanate from discrete sites of expression and elicit concentration-dependent cellular differentiation or proliferation responses. Cellular responses to Hh and the movement of Hh through tissues are both precisely regulated, and abnormal Hh signalling has been implicated in human birth defects and cancer. Hh signalling is mediated by its amino-terminal domain (HhN), which is dually lipidated and secreted as part of a multivalent lipoprotein particle. Reception of the HhN signal is modulated by several cell-surface proteins on responding cells, including Patched (Ptc), Smoothened (Smo), Ihog (known as CDO or CDON in mammals) and the vertebrate-specific proteins Hip (also known as Hhip) and Gas1 (ref. 11). Drosophila Ihog and its vertebrate homologues CDO and BOC contain multiple immunoglobulin and fibronectin type III (FNIII) repeats, and the first FNIII repeat of Ihog binds Drosophila HhN in a heparin-dependent manner. Surprisingly, pull-down experiments suggest that a mammalian Sonic hedgehog N-terminal domain (ShhN) binds a non-orthologous FNIII repeat of CDO. Here we report biochemical, biophysical and X-ray structural studies of a complex between ShhN and the third FNIII repeat of CDO. We show that the ShhN-CDO interaction is completely unlike the HhN-Ihog interaction and requires calcium, which binds at a previously undetected site on ShhN. This site is conserved in nearly all Hh proteins and is a hotspot for mediating interactions between ShhN and CDO, Ptc, Hip and Gas1. Mutations in vertebrate Hh proteins causing holoprosencephaly and brachydactyly type A1 map to this calcium-binding site and disrupt interactions with these partners.

SUBMITTER: McLellan JS

PROVIDER: S-EPMC2679680 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla.

McLellan Jason S JS Zheng Xiaoyan X Hauk Glenn G Ghirlando Rodolfo R Beachy Philip A PA Leahy Daniel J DJ

Nature 20080914 7215

Hedgehog (Hh) proteins specify tissue pattern in metazoan embryos by forming gradients that emanate from discrete sites of expression and elicit concentration-dependent cellular differentiation or proliferation responses. Cellular responses to Hh and the movement of Hh through tissues are both precisely regulated, and abnormal Hh signalling has been implicated in human birth defects and cancer. Hh signalling is mediated by its amino-terminal domain (HhN), which is dually lipidated and secreted a ...[more]

PMID: 18794898

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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.

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The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla.

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The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla.

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