title: Dissection of Tbx1 and Fgf interactions in mouse models of 22q11DS suggests functional redundancy.
abstract: The 22q11 deletion syndrome (22q11DS) is characterized by abnormal development of the pharyngeal apparatus. Mouse genetic studies have identified Tbx1 as a key gene in the etiology of the syndrome, in part, via interaction with the fibroblast growth factor (Fgf) genes. Three murine Fgfs, Fgf3, Fgf8 and Fgf10 are coexpressed in different combinations with Tbx1. They are all strongly downregulated in Tbx1-/- embryos, implicating epistatic interactions. Supporting this, Tbx1 and Fgf8 have been shown to genetically interact in the development of the fourth pharyngeal arch artery (PAA) and Fgf10 was identified to be a direct downstream target of Tbx1. To dissect the epistatic relationships of these genes during embryonic development and the molecular pathogenesis of the Tbx1 mutant phenotype, we generated Fgf10+/-;Tbx1+/- and Fgf3-/-;Tbx1+/- mice. Despite strong hypotheses that Fgf10 is the key gene downstream of Tbx1 in the development of the anterior heart field, we do not find evidence for genetic interaction between Tbx1 and Fgf10. Also, the Fgf3-/-;Tbx1+/- mutant mice do not show an additive phenotype. Furthermore, more severe defects do not occur in Fgf8+/-;Tbx1+/- mutants by crossing in the Fgf3 null allele. There is a possible additive effect only in PAA remodeling in the Fgf10+/-;Tbx1+/-;Fgf8+/- embryos. Our findings underscore the importance of potential functional redundancy with additional Fgfs in the development of the pharyngeal apparatus and cardiovascular system via Tbx1. This redundancy should be considered when looking at individual FGF genes as modifiers of 22q11DS.
authors.affiliation: Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: Vimla S
authors.initials: VS
authors.lastname: Aggarwal
authors.forename: Jun
authors.initials: J
authors.lastname: Liao
authors.forename: Alexei
authors.initials: A
authors.lastname: Bondarev
authors.forename: Thomas
authors.initials: T
authors.lastname: Schimmang
authors.forename: Mark
authors.initials: M
authors.lastname: Lewandoski
authors.forename: Joseph
authors.initials: J
authors.lastname: Locker
authors.forename: Alan
authors.initials: A
authors.lastname: Shanske
authors.forename: Marina
authors.initials: M
authors.lastname: Campione
authors.forename: Bernice E
authors.initials: BE
authors.lastname: Morrow
mesh_terms: D000818:Animals; D019465:Craniofacial Abnormalities / Q000196:embryology; D004062:DiGeorge Syndrome / Q000235:genetics* / Q000473:pathology; D004843:Epistasis, Genetic; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000378:metabolism; D051518:Fibroblast Growth Factor 3 / Q000235:genetics / Q000378:metabolism; D051524:Fibroblast Growth Factor 8 / Q000235:genetics / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006330:Heart Defects, Congenital / Q000196:embryology; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D010614:Pharynx / Q000196:embryology; D010641:Phenotype; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism; D013950:Thymus Gland / Q000002:abnormalities / Q000196:embryology; D013961:Thyroid Gland / Q000002:abnormalities / Q000196:embryology
chemical_list: C496464:Fgf10 protein, mouse; C489197:Fgf3 protein, mouse; C496457:Fgf8 protein, mouse; D051526:Fibroblast Growth Factor 10; D051518:Fibroblast Growth Factor 3; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors