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Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein


The Hedgehog signalling pathway is essential for the development of diverse tissues during embryogenesis1. Signalling is activated by binding of Hedgehog protein to the multipass membrane protein Patched (Ptc)2,3. We have now identified a novel component in the vertebrate signalling pathway, which we name Hip (for Hedgehog-interacting protein) because of its ability to bind Hedgehog proteins. Hip encodes a membrane glycoprotein that binds to all three mammalian Hedgehog proteins with an affinity comparable to that of Ptc-1. Hip-expressing cells are located next to cells that express each Hedgehog gene. Hip expression is induced by ectopic Hedgehog signalling and is lost in Hedgehog mutants. Thus, Hip, like Ptc-1, is a general transcriptional target of Hedgehog signalling. Overexpression of Hip in cartilage, where Indian hedgehog (Ihh) controls growth4, leads to a shortened skeleton that resembles that seen when Ihh function is lost (B. St-Jacques, M. Hammerschmidt & A.P.M., in preparation). Our findings support a model in which Hip attenuates Hedgehog signalling as a result of binding to Hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any Hedgehog signal.

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Figure 1: Sequence analysis of the Hip cDNA.
Figure 2: Analysis of the Hip protein.
Figure 3: Expression of Hip during embryogenesis.
Figure 4: Expression of Hip transcripts in animals with ectopic or defective Hedgehog signalling.
Figure 5: Analysis of skeleton in animals overexpressing Hip in chondrocytes.


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We thank H.-J. Cheng for advice on expression cloning, J.-L. Chen for help with sequencing, B. St-Jacques for Ihh mutant embryos, S. Lee, J. McMahon and M. Bitgood for performing in situ hybridization, N. Wu for pronuclear injection, D. Faria and B. Klumpar for histological section, M. Scott for the Patched-1 expression clone, B. Seed for pCD5IgG1 vector, Y. Yamada for the α1(II) collagen expression vector and M. Sanicola for the RETL1 clone, anti-RETL1 antibody and a protocol for PI–PLC cleavage. We thank past and present members of the McMahon lab for discussion and critical reading of the manuscript. P.-T.C. is a fellow of the Leukemia Society of America. This work was supported by a grant from the NINDS to A.P.M. The GenBank accession number for Hip is AF116865.

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Chuang, PT., McMahon, A. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 397, 617–621 (1999).

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