The Cleft Lip and Palate Defects in Dancer Mutant Mice Result from Gain of Function of the Tbx10 Gene

Cleft lip and palate (CL/P) is a common disfiguring birth defect with complex, poorly understood etiology. Mice carrying a spontaneous mutation, Dancer (Dc), exhibit CL/P in homozygotes and show significantly increased susceptibility to CL/P in heterozygotes [Deol, M. S. & Lane, P. W. (1966) J....

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2004-05, Vol.101 (18), p.7022-7027
Main Authors: Bush, Jeffrey O., Lan, Yu, Jiang, Rulang, Ruddle, Francis H.
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Birth defects
Chromosome Mapping
Cleft Lip - genetics
Cleft Lip - pathology
Cleft Palate - genetics
Cleft Palate - pathology
DNA
Embryos
Exons
Gene expression
Genes
Genetic loci
Genetic mutation
Introns
Messenger RNA
Mice
Mice, Transgenic
Molecular Sequence Data
Mutation
Sequence Analysis, DNA
T-Box Domain Proteins - genetics
T-Box Domain Proteins - metabolism
Transgenic animals
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Summary:Cleft lip and palate (CL/P) is a common disfiguring birth defect with complex, poorly understood etiology. Mice carrying a spontaneous mutation, Dancer (Dc), exhibit CL/P in homozygotes and show significantly increased susceptibility to CL/P in heterozygotes [Deol, M. S. & Lane, P. W. (1966) J. Embryol. Exp. Morphol. 16, 543-558 and Trasler, D. G., Kemp, D. & Trasler, T. A. (1984) Teratology 29, 101-104], providing an animal model for understanding the molecular pathogenesis of CL/P. We genetically mapped Dc to within a 1-cM region near the centromere of chromosome 19. In situ hybridization analysis showed that one positional candidate gene, Tbx10, is ectopically expressed in Dc mutant embryos. Positional cloning of the Dc locus revealed an insertion of a 3.3-kb sequence containing the 5′ region of the p23 gene into the first intron of Tbx10, which causes ectopic expression of a p23-Tbx10 chimeric transcript encoding a protein product identical to a normal variant of the Tbx10 protein. Furthermore, we show that ectopic expression of Tbx10 in transgenic mice recapitulates the Dc mutant phenotype, indicating that CL/P in Dc mutant mice results from the p23 insertion-induced ectopic Tbx10 expression. These results identify gain of function of a T-box transcription factor gene as a mechanism underlying CL/P pathogenesis.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0401025101