MECHANISMS OF REDUCED FERTILITY IN HOXA-10 MUTANT MICE - UTERINE HOMEOSIS AND LOSS OF MATERNAL HOXA-10 EXPRESSION

The establishment of a receptive uterine environment is critical for e mbryonic survival and implantation, One gene that is expressed in the uterus during the peri-implantation period in mice and is required for female fertility is the homeobox gene Hoxa-10. Here we characterize t he periimplantation defects in Hoxa-10 mutant females and investigate functions of Hoxa-10 in the uterine anlage during morphogenesis and in the adult uterus during pregnancy, Examination of pregnancy in Hoxa-1 0 mutant females has revealed failure of implantation as well as resor ption of embryos in the early postimplantation period, Morphologic ana lysis of the mutant uterus has demonstrated homeotic transformation of the proximal 25% into oviduct, Histology and molecular markers confir m this anterior transformation, Furthermore, in situ hybridization sho ws that this region coincides with the anterior limit of embryonic Hox a-10 expression in the urogenital ducts and a parallel transformation is observed in Hoxa-10 mutant males at the junction of the epididymis and ductus deferens, Female fertility could be compromised by either t he homeotic transformation or the absence of Hoxa-10 function in the a dult during pregnancy, To distinguish between these two potential mech anisms of infertility, wildtype blastocysts were transferred into muta nt uteri distal to the transformed region on day 2.5 of pseudopregnanc y. This procedure did not rescue the phenotype, suggesting that adult uterine expression of Hoxa-10 is required during pregnancy, Moreover, when implantation was experimentally delayed, homozygous uteri were ab le to support survival of blastocysts comparable to wild-type controls , indicating that the requirement for Hoxa-10 is intrinsic to implanta tion, While expression of LIF and HB-EGF appears unaffected in the mut ant uteri, a decrease is observed in the intensity and number of blue dye reactions, an indicator of increased vascular permeability in resp onse to implantation, In addition, mutant uteri exhibited decreased de cidualization in response to artificial stimuli, These results show th at Hoxa-10 is required during morphogenesis for proper patterning of t he reproductive tract and in the adult uterus for peri-implantation ev ents.