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The chicken talpid 3 gene encodesa novel protein essentialfor Hedgehog signaling

2006; Cold Spring Harbor Laboratory Press; Volume: 20; Issue: 10 Linguagem: Inglês

10.1101/gad.369106

1549-5477

Megan G. Davey, Ian R. Paton, Yili Yin, Maike Schmidt, Fiona Bangs, David Morrice, Terence G. Smith, Paul Buxton, Despina Stamataki, Mikiko Tanaka, Andrea Münsterberg, James Briscoe, Cheryll Tickle, David W. Burt,

Congenital Ear and Nasal Anomalies

Talpid 3 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 talpid 3 embryos and to identify the talpid 3 gene. We show in several regions of the embryo that the talpid 3 phenotype is completely ligand independent and demonstrate for the first time that talpid 3 is absolutely required for the function of both Gli repressor and activator in the intracellular Hedgehog pathway. We map the talpid 3 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 talpid 3 mutant cells but that Gli3 can still translocate to the nucleus. These results suggest that the talpid 3 protein operates in the cytoplasm to regulate the activity of both Gli repressor and activator proteins.