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The chicken talpid³ gene encodesa novel protein essentialfor Hedgehog signaling

¹ Division of Cell and Developmental Biology, Wellcome Trust Biocentre (WTB), University of Dundee, Dundee DD1 5EH, United Kingdom; ² Department of Genetics and Genomics, Roslin Institute (Edinburgh), Midlothian EH25 9PS, United Kingdom; ³ Division of Biomaterials and Tissue Engineering, Eastman Dental Institute, London WC1X 8LD, United Kingdom; ⁴ Division of Developmental Neurobiology, National Institute for Medical Research, London NW7 1AA, United Kingdom; ⁵ School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, United Kingdom

Talpid³ is a classical chicken mutant with abnormal limb patterning and malformations in other regions of the embryo known to depend on Hedgehog signaling. We combined the ease of manipulating chicken embryos with emerging knowledge of the chicken genome to reveal directly the basis of defective Hedgehog signal transduction in talpid³ embryos and to identify the talpid³ gene. We show in several regions of the embryo that the talpid³ phenotype is completely ligand independent and demonstrate for the first time that talpid³ is absolutely required for the function of both Gli repressor and activator in the intracellular Hedgehog pathway. We map the talpid³ locus to chromosome 5 and find a frameshift mutation in a KIAA0586 ortholog (ENSGALG00000012025), a gene not previously attributed with any known function. We show a direct causal link between KIAA0586 and the mutant phenotype by rescue experiments. KIAA0586 encodes a novel protein, apparently specific to vertebrates, that localizes to the cytoplasm. We show that Gli3 processing is abnormal in talpid³ mutant cells but that Gli3 can still translocate to the nucleus. These results suggest that the talpid³ protein operates in the cytoplasm to regulate the activity of both Gli repressor and activator proteins.

[Keywords: Gli; Hedgehog signaling; chicken; talpid³]

Received October 6, 2005; revised version accepted March 9, 2006.

E-MAIL c.a.tickle{at}dundee.ac.uk; FAX 44-1382-385-386

⁷ E-MAIL Dave.Burt{at}bbsrc.ac.uk; FAX 44-131-440-0434.

Supplemental material is available at http://www.genesdev.org.

Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.369106

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