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Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice


DiGeorge syndrome is characterized by cardiovascular, thymus and parathyroid defects and craniofacial anomalies, and is usually caused by a heterozygous deletion of chromosomal region 22q11.2 (del22q11) (ref. 1). A targeted, heterozygous deletion, named Df(16)1, encompassing around 1 megabase of the homologous region in mouse causes cardiovascular abnormalities characteristic of the human disease2. Here we have used a combination of chromosome engineering and P1 artificial chromosome transgenesis to localize the haploinsufficient gene in the region, Tbx1. We show that Tbx1, a member of the T-box transcription factor family, is required for normal development of the pharyngeal arch arteries in a gene dosage-dependent manner. Deletion of one copy of Tbx1 affects the development of the fourth pharyngeal arch arteries, whereas homozygous mutation severely disrupts the pharyngeal arch artery system. Our data show that haploinsufficiency of Tbx1 is sufficient to generate at least one important component of the DiGeorge syndrome phenotype in mice, and demonstrate the suitability of the mouse for the genetic dissection of microdeletion syndromes.

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Figure 1: Gene targeting experiments for chromosome engineering.
Figure 2: Transgenic rescue of the Df(16)1/+ phenotype and developmental expression of the Tbx1 gene in wild-type embryos.
Figure 3: Tbx1 gene mutagenesis and resulting pharyngeal arch artery phenotype.
Figure 4: The pharyngeal arch phenotype in Tbx1 mutant and compound heterozygous embryos.

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We thank R. Behringer and P. Hastings for discussions and reading of the manuscript, and Y.-C. Cheah, S. Carattini-Rivera, G. C. Schuster, S.-S. Cheah and C. Roberts for technical contributions. A.B. is an investigator with the Howard Hughes Medical Institute. This work was funded in part by grants from the National Heart, Lung and Blood Institute and (to A.B.), from the American Heart Association Texas Affiliate (to E.A.L.), and from the British Heart Foundation and Wellcome Trust (to P.J.S.). Support from the Baylor Mental Retardation Research Center is also acknowledged.

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Correspondence to Antonio Baldini.

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Lindsay, E., Vitelli, F., Su, H. et al. Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 410, 97–101 (2001).

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