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The Developmental Effects of Six1 Mutations on the Otic Expression of Putative Target Genes in Xenopus Embryos Público

Point mutations in the SIX1 gene play a major role in branchio-oto-renal spectrum disorders (BORSD), a birth defect that leads to mixed hearing loss. Permanent malfunction of the middle and inner ear can be attributed to the malformation of the ear’s ossicles and middle ear space, as well as hypoplasia in inner ear structures. As the Six1 gene is heavily involved in the regulation of cranial placode development that gives rise to the ear, the morphological presentation of BORSD can be explained by the interaction between Six1 mutants and their target genes. Using affected tissues, including the cranial neural crest and otic placode, one can trace the involvement of the mutant Six1 gene to its interactions with neural crest cells and branchial arch progenitor cells. Within these cellular regions, there are proposed candidate genes that are targets of Six1: prdm1 and eya2. Four BORSD mutations were engineered in the Xenopus Six1 gene (V17E, Y129C, R110W, and W122R), which is 100% identical to the human SIX1 gene in two mutated regions of the Six1 protein. Mutants were expressed in a wild-type background in Xenopus laevis embryos in order to find any alteration in the expression of the target genes. Results were consistent with previous studies: Six1 mutants were transcriptionally deficient and had deleterious effects in otic development. However, interactions between specific mutants and target genes varied, resulting in variable phenotypic expression in the otocyst.

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