Dose-dependent interaction of Tbx1 and Crkl and locally aberrant RA signaling in a model of del22q11 syndrome

被引:165
作者
Guris, DL
Duester, G
Papaioannou, VE
Imamoto, A [1 ]
机构
[1] Univ Chicago, Ben May Inst Canc Res, Chicago, IL 60637 USA
[2] Univ Chicago, Ctr Mol Oncol, Chicago, IL 60637 USA
[3] Univ Chicago, Comm Dev Biol, Chicago, IL 60637 USA
[4] Burnham Inst, OncoDev Biol Program, La Jolla, CA 92037 USA
[5] Columbia Univ Coll Phys & Surg, Dept Genet & Dev, New York, NY 10032 USA
关键词
D O I
10.1016/j.devcel.2005.12.002
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:81 / 92
页数:12
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