An ultra-conserved element in Hoxa2 is required for the normal expression of Hoxa3 and normal thymus development (HEM7P.223)

Abstract

Abstract We analyzed thymus development in a Hoxa2 mutant mouse (Hoxa21) that carries a deletion of an ultraconserved element in the protein coding sequence of Hoxa2. Our phenotypic analysis revealed that the Hoxa21 mutants exhibit hypoplastic and ectopic thymii. Further analysis demonstrated delayed Foxn1 expression within the developing thymus of the mutants. These phenotypes resemble the alterations in thymus development found in Hoxa3 mutant embryos. Intriguingly, analysis of thymus development in mutants carrying a different Hoxa2 null allele that contains an intact ultraconserved element (Hoxa22) revealed no alteration in thymus development. This findings suggested that the abnormal thymus development seen in the Hoxa21 mutants may be due to alterations in Hoxa3 expression. Consistent with this hypothesis Hoxa21 mutants exhibited greatly reduced Hoxa3 expression in neural crest-derived mesenchyme and pharyngeal endoderm, embryonic cell types required for normal thymus development. In addition analysis of Hoxa21+/- Hoxa3 null/+ compound heterozygotes revealed thymus phenotypes that were very similar to Hoxa3-deficient mutants. These data suggest that Hoxa2, although expressed in thymic primordium, does not play a direct role in thymic organogenesis. Our results suggest that the ultraconserved enhancer element located the first exon of Hoxa2 is necessary for normal Hoxa3 expression in cell types necessary for normal thymus development.