Dose-dependent interaction of Tbx1 and Crkl and locally aberrant RA signaling in a model of del22q11 syndrome
Dose-dependent interaction of Tbx1 and Crkl and locally aberrant RA signaling in a model of del22q11 syndrome
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DOI：
10.1016/j.devcel.2005.12.002
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发表时间：
2006-01-01
影响因子：
11.8
通讯作者：
Imamoto, A
中科院分区：
文献类型：
--
作者：
Guris, DL;Duester, G;Imamoto, A
22q11缺失（del22q11）综合征的遗传特征是22q11染色体的杂合缺失，临床表现为主动脉弓、心脏、胸腺和甲状旁腺的先天性畸形，称为DiGeorge综合征（DGS）。在这里，我们报告了两个22q11基因CRKL和TBX1的小鼠同源物的复合杂合性，与任何一个位点的杂合性相比，导致dgs样表型的外显率和表达性显著增加。此外，我们发现这两个基因在咽部分割、沿前后轴的咽器模式以及视黄酸（RA）代谢和信号传导的局部调节中具有关键的剂量依赖性功能。我们可以部分地挽救Crke中DGS的一个显著特征（+/-）；Tbx1（+/-）胚胎通过基因减少胚胎中RA的产生量。因此，我们认为del22q11是一种连续基因综合征，涉及CRKL和TBX1的剂量敏感相互作用和局部异常RA信号。
22q11 deletion (del22q11) syndrome is characterized genetically by heterozygous deletions within chromosome 22q11 and clinically by a constellation of congenital malformations of the aortic arch, heart, thymus, and parathyroid glands described as DiGeorge syndrome (DGS). Here, we report that compound heterozygosity of mouse homologs of two 22q11 genes, CRKL and TBX1, results in a striking increase in the penetrance and expressivity of a DGS-like phenotype compared to heterozygosity at either locus. Furthermore, we show that these two genes have critical dose-dependent functions in pharyngeal segmentation, patterning of the pharyngeal apparatus along the anteroposterior axis, and local regulation of retinoic acid (RA) metabolism and signaling. We can partially rescue one salient feature of DGS in Crke(+/-);Tbx1(+/-) embryos by genetically reducing the amount of RA produced in the embryo. Thus, we suggest that del22q11 is a contiguous gene syndrome involving dose-sensitive interaction of CRKL and TBX1 and locally aberrant RA signaling.