Foxi3, a member of the Forkhead box (FOX) family of transcription factors, is characterized by the presence of a conserved 'forkhead' or 'winged-helix' DNA-binding domain. It plays a critical role in ectodermal patterning, especially in the fate restriction of placodal lineages at the neural plate border. It is involved in the development of posterior placodes, such as the otic and epibranchial placodes, and is expressed in the progenitors of craniofacial placodes, epidermal placodes, and the ectoderm and endoderm of the pharyngeal arch region [3,5,6,8].

In gene knockout studies, Foxi3 mutant mice do not form otic placodes, as early molecular markers are altered, and there is a lack of thickened placodal ectoderm, otic cup, or otocyst. Some pre-placodal genes downstream of Foxi3 are not expressed, and the ectoderm shows increased apoptosis. Also, Fgf signals for otic placode induction are received but not correctly interpreted in Foxi3 mutants [8]. In Tbx1+/-;Foxi3+/- double heterozygous mouse embryos, thymus and parathyroid gland defects similar to those in 22q11.2 deletion syndrome patients are observed [7]. In humans, pathogenic variants in FOXI3 cause craniofacial microsomia (CFM), with missense variants in the nuclear localization sequence affecting subcellular localization and loss-of-function variants leading to microtia and mandibular hypoplasia. FOXI3 haploinsufficiency can result in T-cell lymphopenia [1,2,4].

In conclusion, Foxi3 is essential for the development of posterior placodes, the proper formation of craniofacial structures, and potentially thymus development. Mouse models with Foxi3 gene knockout or knockdown have been crucial in revealing its role in these processes and in understanding human diseases like CFM and T-cell lymphopenia.