INTRODUCTION Tbx1, a T-box putative transcription factor, is required for the segmentation of the pharyngeal apparatus, and homozygous mutation causes multiple developmental defects, including cardiovascular, craniofacial, ear, thymic and parathyroid defects (Jerome and Papaioannou, 2001; Lindsay et al., 2001; Vitelli et al., 2002). Tbx1 expression has been extensively analyzed by RNA in situ hybridization (Chapman et al., 1996; Garg et al., 2001; Jerome and Papaioannou, 2001; Lindsay et al., 2001; Merscher et al., 2001) and by a lacZ reporter knocked into the endogenous locus (Vitelli et al., 2002). The expression pattern is dynamic during development and is mainly localized in the head mesenchyme, pharyngeal endoderm, core mesenchyme of the cranial pharyngeal arches, outflow tract of the heart, mesenchyme surrounding the dorsal aortae, otocyst and sclerotome. Tbx1 haploinsufficiency causes aortic arch patterning defects in mice (Jerome and Papaioannou, 2001; Lindsay et al., 2001; Merscher et al., 2001) of the same type as those observed in a mouse model, named Df1/+ of the chromosomal deletion occurring in individuals with DiGeorge syndrome (Lindsay et al., 1999). The mouse deletion Df1 and the human deletion del22q11 both include Tbx1, making this gene the most likely candidate for a pathogenetic role in this syndrome. Tbx1 haploinsufficiency causes early growth and remodeling defects of the fourth pharyngeal arch arteries (PAAs), first evident at embryonic day (E) 10.5. The caudal PAAs (third, fourth and sixth) form sequentially as symmetric vessels connecting the aortic sac with the dorsal aortae. From ~E11.5, the PAAs undergo a major, asymmetric remodeling that leads to the mature aortic arch and great vessel patterning (Srivastava and Olson, 2000). In particular, the left fourth PAA contributes to the section of the mature aortic arch between the origins of the left common carotid artery and the left subclavian artery. Developmental failure of the left fourth PAA causes interruption of the aortic arch type B (IAA-B). The right fourth PAA provides the connection of the right subclavian artery with the innominate artery. Developmental failure of the right fourth PAA causes aberrant origin of the right subclavian artery, most commonly from the descending aorta, via a retroesophageal vessel. 4605 Development 129, 4605-4611 (2002) Printed in Great Britain © The Company of Biologists Limited 2002 DEV14544 Tbx1 haploinsufficiency causes aortic arch abnormalities in mice because of early growth and remodeling defects of the fourth pharyngeal arch arteries. The function of Tbx1 in the development of these arteries is probably cell non- autonomous, as the gene is not expressed in structural components of the artery but in the surrounding pharyngeal endoderm. We hypothesized that Tbx1 may trigger signals from the pharyngeal endoderm directed to the underlying mesenchyme. We show that the expression patterns of Fgf8 and Fgf10, which partially overlap with Tbx1 expression pattern, are altered in Tbx1 –/– mutants. In particular, Fgf8 expression is abolished in the pharyngeal endoderm. To understand the significance of this finding for the pathogenesis of the mutant Tbx1 phenotype, we crossed Tbx1 and Fgf8 mutants. Double heterozygous Tbx1 +/– ;Fgf8 +/– mutants present with a significantly higher penetrance of aortic arch artery defects than do Tbx1 +/– ;Fgf8 +/+ mutants, while Tbx1 +/+ ;Fgf8 +/– animals are normal. We found that Fgf8 mutation increases the severity of the primary defect caused by Tbx1 haploinsufficiency, i.e. early hypoplasia of the fourth pharyngeal arch arteries, consistent with the time and location of the shared expression domain of the two genes. Hence, Tbx1 and Fgf8 interact genetically in the development of the aortic arch. Our data provide the first evidence of a genetic link between Tbx1 and FGF signaling, and the first example of a modifier of the Tbx1 haploinsufficiency phenotype. We speculate that the FGF8 locus might affect the penetrance of cardiovascular defects in individuals with chromosome 22q11 deletions involving TBX1. Key words: Pharyngeal endoderm, Pharyngeal arch arteries, Phenotypic modifiers SUMMARY DEVELOPMENT AND DISEASE A genetic link between Tbx1 and fibroblast growth factor signaling Francesca Vitelli 1 , Ilaria Taddei 1 , Masae Morishima 1 , Erik N. Meyers 2 , Elizabeth A. Lindsay 1 and Antonio Baldini 1,3 1 Department of Pediatrics (Cardiology), Baylor College of Medicine, Houston TX 77030, USA 2 Department of Pediatrics and Cell Biology, Duke University Medical Center, Durham NC 27710, USA 3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston TX 77030, USA *Author for correspondence (e-mail: baldini@bcm.tmc.edu) Accepted 1 July 2002