Tbx1 and Foxi3 genetically interact in the third pharyngeal pouch endoderm required for thymus and parathyroid development

The mechanisms required for segmentation of the pharyngeal apparatus to individual arches are not precisely delineated in mammalian species. Here, using conditional mutagenesis, we found that two transcription factor genes, Tbx1 , the gene for 22q11.2 deletion syndrome and Foxi3 , genetically interact in the third pharyngeal pouch endoderm for thymus and parathyroid gland development. We found that Tbx1 is autonomously required for the endoderm to form a temporary multilayered epithelium while invaginating. E-cadherin for adherens junctions remains expressed and cells in the apical boundary express ZO-1. Foxi3 is required autonomously to modulate proliferation and promote later restoration of the endoderm to a monolayer once the epithelia meet after invagination. Completion of this process cooccurs with expression of Alcam needed to stabilize adherens junctions and extracellular, Fibronectin. These processes are required in the third pharyngeal pouch to form the thymus and parathyroid glands, disrupted in 22q11.2 deletion syndrome patients.