Murine Hox11 Paralogs are Required for Metanephric Kidney Development

In mice containing mutant alleles of either Hoxa11 or Hoxd11, kidney development appears grossly normal while animals carrying the combined, double mutations display hypoplastic defects in the newborn kidney. Based on many observations of Hox gene functional redundancy and the apparent functional overlap of Hoxa11 and Hoxd11 in kidney development, mice were created in which all three Hox11 paralogs, Hoxa11, Hoxc11, and Hoxd11, were introduced into a single animal. Combination of all three mutant alleles results in a complete loss of ureteric bud formation, one of the earliest steps in metanephric development. By E10.5, aggregation of the metanephric blastema and expression of Pax2 and WT1, two of the earliest proteins required for metanephric development, appears normal in both control and triple-mutant mice. Within the next 24 hours of development, the ureter normally invades the metanephric blastema, which subsequently condenses and becomes induced. In the triple-mutants, however, ureteric budding from the Wolffian duct fails to initiate and the metanephric blastema undergoes apoptosis by E11.5. This demonstrates that the Hox11 paralogs are critically important in the earliest processes of metanephric development. Further molecular characterization in this well-defined system should allow us to understand, more specifically, the role of these Hox11 paralogs in the development of this organ.