Vitelli Francesca, Morishima Masae, Taddei Ilaria, Lindsay Elizabeth A, Baldini Antonio
Department of Pediatrics (Cardiology), Baylor College of Medicine, Houston, TX 77030, USA.
Hum Mol Genet. 2002 Apr 15;11(8):915-22. doi: 10.1093/hmg/11.8.915.
TBX1 is the major candidate gene for DiGeorge syndrome (DGS). Mouse studies have shown that the Tbx1 gene is haploinsufficient, as expected for a DGS candidate gene, and that it is required for the development of pharyngeal arches and pouches, as predicted by the DGS clinical phenotype. However, a detailed analysis of the cardiovascular phenotype associated with Tbx1 mutations has not been reported. Here we show that Tbx1 deficiency causes a number of distinct vascular and heart defects, suggesting multiple roles in cardiovascular development - specifically formation and growth of the pharyngeal arch arteries, growth and septation of the outflow tract of the heart, interventricular septation, and conal alignment. Comparison of phenotype and gene expression using a Tbx1-lacZ reporter allele supports a cell-autonomous function in the growth of the pharyngeal apparatus, and a cell non-autonomous function in the growth and early remodeling of the pharyngeal arch arteries. Our data do not support a direct role of neural crest cells in the pathogenesis of the Tbx1 mutant phenotype; however, these cells, and the cranial nerves, are misdirected. We hypothesize that this is due to the lack of a guidance role from the pouch endoderm, which is missing in these mutants.
TBX1是22q11.2缺失综合征（DGS）的主要候选基因。小鼠研究表明，Tbx1基因单倍剂量不足，这符合DGS候选基因的预期，并且如DGS临床表型所预测的那样，它是咽弓和咽囊发育所必需的。然而，尚未有关于与Tbx1突变相关的心血管表型的详细分析报道。在此我们表明，Tbx1缺陷会导致多种不同的血管和心脏缺陷，提示其在心血管发育中具有多种作用——特别是咽弓动脉的形成和生长、心脏流出道的生长和分隔、室间隔分隔以及圆锥排列。使用Tbx1 - lacZ报告基因等位基因对表型和基因表达进行比较，支持其在咽器官生长中具有细胞自主功能，而在咽弓动脉生长和早期重塑中具有细胞非自主功能。我们的数据不支持神经嵴细胞在Tbx1突变体表型发病机制中起直接作用；然而，这些细胞和颅神经的走向发生了错误。我们推测这是由于这些突变体中缺失的咽囊内胚层缺乏引导作用所致。
