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First published online 21 July 2004
doi: 10.1242/dev.01257

This Article Figures Only Full Text Full Text (PDF) Supplemental Figures A retraction has been published All Versions of this Article: dev.01257v1 131/16/4021    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in Development Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tian, H. Articles by McMahon, A. P. Search for Related Content PubMed PubMed Citation Articles by Tian, H. Articles by McMahon, A. P. Social Bookmarking                         What's this?

Dose dependency of Disp1 and genetic interaction between Disp1 and other hedgehog signaling components in the mouse

Department of Molecular and Cellular Biology, The Biolabs, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA

^* Author for correspondence (e-mail: amcmahon{at}mcb.harvard.edu)

Accepted 7 May 2004

Genetic analyses in Drosophila have demonstrated that a transmembrane protein Dispatched (Disp) is required for the release of lipid-modified Hedgehog (Hh) protein from Hh secreting cells. Analysis of Disp1 null mutant embryos has demonstrated that Disp1 plays a key role in hedgehog signaling in the early mouse embryo. Here we have used a hypomorphic allele in Disp1(Disp1²), to extend our knowledge of Disp1 function in Hh-mediated patterning of the mammalian embryo. Through genetic combinations with null alleles of patched 1 (Ptch1), sonic hedgehog (Shh) and Indian hedgehog (Ihh), we demonstrate that Disp1 genetically interacts with Hh signaling components. As Disp1 activity is decreased we see a progressive increase in the severity of hedgehog-dependent phenotypes, which is further enhanced by reducing hedgehog ligand levels. Analysis of neural tube patterning demonstrates a progressive loss of ventral cell identities that most likely reflects decreased Shh signaling as Disp1 levels are attenuated. Conversely, increasing available Shh ligand by decreasing Ptch1 dosage leads to the restoration of ventral cell types in Disp1^2/2 mutants. Together, these studies suggest that Disp1 actively regulates the levels of hedgehog ligand that are available to the hedgehog target field. Further, they provide additional support for the dose-dependent action of Shh signaling in patterning the embryo. Finally, in-vitro studies on Disp1 null mutant fibroblasts indicate that Disp1 is not essential for membrane targeting or release of lipid-modified Shh ligand.

Key words: Dispatched, Sonic hedgehog, Patched, Hypomorph, Mouse, Morphogenesis

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