Abnormal Uterine Stromal and Glandular Function Associated with Maternal Reproductive Defects in Hoxa-11 Null Mice1

Abstract

Here we describe in detail both the expression of Hoxa-11 in the wild-type mouse uterus and the defects resulting in maternal reproductive failure of Hoxa-11 null female mice. The Hoxa-11 gene is expressed at peak levels in uterine stromal cells during metestrus. Hoxa-11 transcripts were induced beginning on Day 2 of gestation in the stromal cells underlying the uterine epithelium and appeared in the secondary decidual zone between Days 6 and 8 of gestation. At early gestational stages, stromal, decidual, and glandular cell development were deficient in Hoxa-11 null uteri in comparison to wild-type as assessed by histology and immunohistochemical localization of the decidual cell marker epitope, stage-specific embryonic antigen-3 (SSEA-3). Both steroid-induced uterine stromal and glandular cell proliferation as well as oil-induced stromal decidualization after induction of pseudopregnancy were deficient in mutant uteri. Moreover, both Western blotting and immunohistochemistry demonstrated that the burst of glandular leukemia inhibitory factor (LIF) found in normal pregnant uteri at Day 4.5 of gestation was absent in Hoxa-11-deficient uteri. The LIF burst was also not observed in the uteri of bilaterally ovariectomized, hormonally stimulated Hoxa-11 mutants. These results demonstrate that the Hoxa-11 gene is required for normal uterine stromal cell and glandular differentiation during pregnancy, as is the presence of the steroid-induced glandular LIF burst initiating embryo implantation.

The Role ofHoxGenes in Female Reproductive Tract Development, Adult Function, and Fertility

“…As described above, Hoxa10/HOXA10 and Hoxa11/HOXA11 are expressed in endometrial glands and stroma throughout the estrus/menstrual cycle. These two HOX genes are essential for embryo implantation in both mice and humans (Hsieh-Li et al 1995;Satokata et al 1995;Benson et al 1996;Gendron et al 1997). Targeted mutation of either Hoxa10 or Hoxa11 in the mice leads to infertility related to defects in uterine receptivity.…”

Identification of transcription factors at the site of implantation in the later stages of murine pregnancy

“…Hoxa11 expression has been shown to peak between gestational days 6 and 8 in the decidua (Gendron et al 1997). To the best of our knowledge, this work represents In situ hybridization using sense probe for Hoxa10.…”

“…Studies in knockout mice demonstrate that both transcription factors are essential for uterine receptivity and implantation (Hsieh-Li et al 1995, Satokata et al 1995, Benson et al 1996, Gendron et al 1997, Bagot et al 2000. The location and regulation of Hoxa10 and Hoxa11 in humans is consistent with a similar role in human implantation as well (Taylor et al 1998, 1999a, 1999b, Sakkas et al 2003.…”

Global Analysis of Genes Regulated by HOXA10 in Decidualization Reveals a Role in Cell Proliferation.

“…Over the years, the decidualization process has been studied extensively and the use of transgenic mice has not only demonstrated its necessity for pregnancy but has made it possible to identify critical genes involved in this process. The genes important for decidualization identified thus far include progesterone receptor A (Lydon et al, 1995), homeobox (HOX) A10 (Satokata et al, 1995), cyclooxygenase 2 (Lim et al, 1997), leukemia inhibitory factor (Stewart et al, 1992;Stewart and Cullinan 1997), interleukin 11 receptor (Robb et al, 1998), Hoxa11 (Gendron et al, 1997), FK506 binding protein 4 (Tranguch et al, 2007), CCAAT/enhancer binding protein beta (Mantena et al, 2006), Indian Hedgehog (Lee et al, 2006), steroid receptor coactivator-1 and steroid receptor coactivator-2 and -1 (Mukherjee et al, 2006).…”