Characterization of Hoxa-10/Hoxa-11 transheterozygotes reveals functional redundancy and regulatory interactions

Hox genes show related sequences and overlapping expression domains that of ten reflect functional redundancy as well as a common evolutionary origin. To accurately define their functions, it has become necessary to compare ph enotypes of mice with single and multiple Hox gene mutations. Here, we focu s on two Abd-B-type genes, Hoxa-10 and Hoxa-11, which are coexpressed in de veloping vertebrae, limbs, and reproductive tracts. To assess possible func tional redundancy between these two genes, Hoxa-10/Hoxa-11 transheterozygot es were produced by genetic intercrosses and analyzed. This compound mutati on resulted in synergistic defects in transheterozygous limbs and reproduct ive tracts, but not in vertebrae. In the forelimb, distal radial/ulnar thic kening and pisiform/triangular carpal fusion were observed in 35 and 21% of transheterozygotes, respectively, but were effectively absent in Hoxa-10 a nd Hoxa-11 +/- forelimbs. In the hindlimb, distal tibial/fibular thickening and loss of tibial/fibular fusion were observed in >80% of transheterozygo tes but in no Hoxa-10 or Hoxa-11 +/- hindlimbs, and all transheterozygotes displayed reduced medial patellar sesamoids, compared to modest incidences in Hoxa-10 and Hoxa-11 +/- mutants. Furthermore, while the reproductive tra cts of Hoxa-10 and Hoxa-11 single heterozygous mutants of both sexes were p rimarily unaffected, male transheterozygotes displayed cryptorchidism and a bnormal tortuosity of the ductus deferens, and female transheterozygotes ex hibited abnormal uterotubal junctions and narrowing of the uterus. In addit ion we observed that the targeted mutations of Hoxa-10 and Hoxa-11 each aff ected the expression of the other gene in the developing prevertebra and re productive tracts. These results provide a measure of the functional redund ancy of Hoxa-10 and Hoxa-11 and a deeper understanding of the phenotypes re sulting in the single mutants and help elucidate the regulatory interaction s between these two genes. (C) 2000 Academic Press.