Function of transcription factors in the evolution and development of pharyngeal organs
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Diversity of body plan has long been a fascinating topic of study. Changes in the Hox genes, especially in the cis-regulatory elements, are believed to contribute to morphological evolution. Hox genes encode a family of transcription factors that play conserved roles in patterning the body plan of metazoan embryos. A large number of studies have revealed the functional equivalence between paralogous and orthologous Hox proteins in distant animals. In this thesis study, for the first time the functional equivalence of Hox proteins is tested by expressing a Hox gene from an evolutionarily “lower” organism to a “higher” organism by precise gene swapping. Zebrafish Hoxa3a protein expressed from the mouse Hoxa3 locus complements the mouse Hoxa3 null mutant phenotype in some tissues, but provides null function in the development of thymus, parathyroid and cranial nerve. Therefore, the mouse Hoxa3 and zebrafish Hoxa3a proteins are functionally distinct despite sharing a highly conserved homeodomain sequence. We further mapped the functional difference to the C-terminal domain of Hoxa3a. Our data suggest that neofunctionalization of Hox proteins might be a key aspect of the evolution of different vertebrate body plans. Hoxa3 and Foxn1 are two transcription factors that play critical roles in thymus development. In Hoxa3 knockout mice, which lack the thymus organ, the expression of Foxn1 is never initiated in the pharyngeal region. Foxn1 is both necessary and sufficient for fetal thymic epithelial cells (TECs) differentiation, but its postnatal function is unknown. In this study, a novel allele of Foxn1, Foxn1lacZ, was shown to down-regulate Foxn1 expression postnatally. We showed that down-regulation of Foxn1 below 50% of normal levels caused degeneration of thymic organization and reduced T cell production, which resembles premature thymus aging. We also showed that specific TEC subsets that express higher Foxn1 levels are most sensitive to its down-regulation, resulting in changes to the postnatal thymic microenvironment and T cell development. These results provide the first functional evidence that Foxn1 is required to maintain the postnatal thymus in a dosage sensitive manner, and hence provide important information for understanding the molecular mechanism of thymus homeostasis and involution.