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Fn1 Regulates the Third Pharyngeal Pouch Patterning and Morphogenesis

The parathyroid and thymus are derived from the common primordia, the third pharyngeal pouch. During their development, endodermal cells actively interact with surrounding mesenchymal cells, mainly derived from neural crest cells (NCCs). However, the mechanism by which NCCs regulate the development of the third pharyngeal pouch remains largely unknown. In this study, we showed that fibronectin 1 (Fn1), which is synthesized by NCCs, modulates the functions of NCCs in the third pharyngeal pouch patterning and in the morphogenesis of the thymus/parathyroid. Loss of Fn1 in NCCs leads to decreased Foxn1 expression in the presumptive thymus domain at E11.5. In the mutant, we detected upregulation of the Hedgehog signaling activity in the presumptive parathyroid domain and downregulation of Bmp4 in the presumptive thymus domain. Tbx1, a Hedgehog signaling target gene in endoderm development, was ectopically expanded to the presumptive mutant thymus domain at E11.5. Fgf10, an important gene regulating the proliferation of endoderm development, was downregulated in the mutant NCCs. At later organogenesis stages, derivatives of the third pharyngeal pouch endoderm of mutant embryos were abnormal, showing conditions such as hypoparathyroidism, hypoplastic thymus, and ectopic thymus and parathyroid. These data support that Fn1 plays an important role in NCCs by regulating the patterning of the third pharyngeal pouch and morphogenesis of the thymus/parathyroid.