THE ROLE OF HOXA-3 IN MOUSE THYMUS AND THYROID DEVELOPMENT

Targeted disruption of Hoxa-3 results in a number of regionally restri cted defects in tissues and structures derived from or patterned by me senchymal neural crest. However, analysis of mutant embryos with injec tions of a carbocyanine dye or with molecular markers that label these cells indicates that neither the amount nor the migration patterns of this neural crest population are grossly affected. Therefore, it appe ars that the loss of Hoxa-3 affects the intrinsic capacity of this neu ral crest cell population to differentiate and/or to induce proper dif ferentiation of the surrounding pharyngeal arch and pouch tissues. Hox a-3 mutant mice are athymic and show thyroid hypoplasia. Thymus develo pment is first evident as an expansion of mesenchymal neural crest in the posterior part of the 3rd pharyngeal pouch. Prior to this expansio n, a marked reduction in pax-1 expression is observed in these cells i n the mutant embryos. As pax-1 mutant mice also show thymic hypoplasia , these results suggest that Hoxa-3 may be required to maintain pax-1 expression in these cells and that the reduction of pax-1 expression i s part of the athymic teleology in Hoxa-3 mutant mice. The thyroid gla nd is formed from the fusion of two structures of separate embryonic o rigin, the thyroid diverticulum, which is formed from endodermal epith elium in the floor of the pharynx, and the ultimobranchial body, forme d from mesenchymal neural crest in the 4th pharyngeal pouch. Both of t hese sites express Hoxa-3 and are defective in mutant mice, Often a ve sicle is observed in mutant mice that is exclusively composed of calci tonin-producing cells, suggesting the persistence of an ultimobranchia l body. Both aspects of the thyroid phenotype show variable expressivi ty among mutant animals, even on the two sides of the same mutant anim al. This variability suggests the presence of a compensating gene or g enes, whose utilization is stochastic. A reasonable candidate for prov iding this compensatory function is the paralogous gene Hoxb-3.