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We investigated whether  Tbx1 , the gene for 22q11.2 deletion syndrome (22q11.2DS) and  Foxi3 , both required for segmentation of the pharyngeal apparatus (PA) to individual arches, genetically interact. We found that all  Tbx1   +/-   ;Foxi3   +/-   double heterozygous mouse embryos had thymus and parathyroid gland defects, similar to those in 22q11.2DS patients. We then examined  Tbx1  and  Foxi3  heterozygous, null as well as conditional  Tbx1   Cre   and  Sox17   2A-iCre/+   null mutant embryos. While  Tbx1   Cre/+   ;Foxi3   f/f   embryos had absent thymus and parathyroid glands,  Foxi3   -/-   and  Sox17   2A-iCre/+   ;Foxi3   f/f   endoderm conditional mutant embryos had in addition, interrupted aortic arch type B and retroesophageal origin of the right subclavian artery, which are all features of 22q11.2DS.  Tbx1   Cre/+   ;Foxi3   f/f   embryos had failed invagination of the third pharyngeal pouch with greatly reduced  Gcm2  and  Foxn1  expression, thereby explaining the absence of thymus and parathyroid glands. Immunofluorescence on tissue sections with E-cadherin and ZO-1 antibodies in wildtype mouse embryos at E8.5-E10.5, revealed that multilayers of epithelial cells form where cells are invaginating as a normal process. We noted that excessive multilayers formed in  Foxi3   -/-  ,  Sox17   2A-iCre/+   ;Foxi3   f/f   as well as  Tbx1  null mutant embryos where invagination should have occurred. Several genes expressed in the PA epithelia were downregulated in both  Tbx1  and  Foxi3  null mutant embryos including Notch pathway genes  Jag1 ,  Hes1 , and  Hey1 , suggesting that they may, along with other genes, act downstream to explain the observed genetic interaction. We found Alcam and Fibronectin extracellular matrix proteins were reduced in expression in  Foxi3  null but not  Tbx1  null embryos, suggesting that some, but not all of the downstream mechanisms are shared.

Tbx1 and Foxi3 genetically interact in the pharyngeal pouch endoderm in a mouse model for 22q11.2 deletion syndrome