The cleft lip and palate defects in Dancer mutant mice result from gain of function of the Tbx10 gene
The cleft lip and palate defects in Dancer mutant mice result from gain of function of the Tbx10 gene
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DOI：
10.1073/pnas.0401025101
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发表时间：
2004-05-04
影响因子：
11.1
通讯作者：
Jiang, RL
中科院分区：
文献类型：
--
作者：
Bush, JO;Lan, Y;Jiang, RL
唇腭裂（CL/P）是一种常见的毁容性出生缺陷，病因复杂，知之甚少。携带自发突变Dancer（Dc）的小鼠在纯合子中表现出CL/P，并且在杂合子中表现出对CL/P的显著增加的易感性[Deol，M. S. & Lane，P. W. 05 The Dog of the Women（1966）MorphoL 16，543-558和Trasler，D. G.，肯普，D. & Trasler，T. A.（1984）Teratology 29，101-1041，提供了用于理解CL/P的分子发病机理的动物模型。我们将Dc遗传定位在染色体19的着丝粒附近的1-cM区域内。原位杂交分析表明，一个位置的候选基因，Tbx 10，异位表达在Dc突变胚胎。Dc基因座的定位克隆揭示了含有p23基因5 ′区的3.3kb序列插入到Tbx 10的第一内含子中，这导致编码与Tbx 10蛋白的正常变体相同的蛋白产物的p23-Tbx 10嵌合转录物的异位表达。此外，我们发现，异位表达的Tbx 10在转基因小鼠重演的Dc突变体的表型，表明CL/P在Dc突变小鼠的结果从p23插入诱导的异位Tbx 10的表达。这些结果确定获得的功能的T-盒转录因子基因的机制CL/P的发病机制。
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, 101-1041, 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.