Human Molecular Genetics, 2002, Vol. 11, No. 8 915-922
© 2002 Oxford University Press
Tbx1 mutation causes multiple cardiovascular defects and disrupts neural crest and cranial nerve migratory pathways
1Department of Pediatrics (Cardiology) 2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
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.
* To whom correspondence should be addressed at: Department of Pediatrics (Cardiology), Baylor College of Medicine, One Baylor Plaza, Room 830E, Mail stop BCM320, Houston, TX 77030, USA. Tel: +1 713 798 6519; Fax: +1 713 798 1483; Email: baldini{at}bcm.tmc.edu
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