Disease relevance of Hoxa10

• We tested whether transgenic over expression of Insl3 can reverse inguinoscrotal cryptorchidism in mice deficient in Gnrhr or Hoxa10 genes [1].
• Null mutation of Hoxa-10 in the mouse causes both male and female infertility [2].
• Mice with a targeted mutation of the Hoxa10 gene demonstrate uterine factor infertility [3].
• The dramatic decrease of HOXA10 in response to IL-1beta or thrombin may contribute to progestin resistance in preterm labor, mimicking progesterone resistance seen in Hoxa10(-/-) mice [4].

High impact information on Hoxa10

• We show here that expression of Hoxa10 in the presomitic mesoderm is sufficient to confer a Hox group 10 patterning program to the somite, producing vertebrae without ribs, an effect not achieved when Hoxa10 is expressed in the somites [5].
• Cryptorchidism and homeotic transformations of spinal nerves and vertebrae in Hoxa-10 mutant mice [6].
• In competitive transplantation assays, Hoxa-9-/- cells showed an 8-fold reduction in multilineage long-term repopulating ability, a defect not seen in marrow cells deficient for the adjacent Hoxa-10 gene [7].
• Finally, a binding site selection identified the sequence AA(A/T)TTTTATTAC as the Hoxa-10 homeodomain consensus binding site, with a TTAT core sequence [8].
• Both Hoxa-10 transcripts demonstrated identical patterns of expression in the posterior body and proximal limb bud, differentiating them from AbdB morphogenetic and regulatory transcripts and suggesting a role with other AbdB Hox genes in the patterning of these structures [8].

Biological context of Hoxa10

• Regulation of smooth muscle-specific gene expression by homeodomain proteins, Hoxa10 and Hoxb8 [9].
• Using degenerate reverse transcription-PCR coupled to cDNA library screening we identified two homeodomain proteins, Hoxa10 and Hoxb8, which are expressed in adult mouse smooth muscle tissues [9].
• Using the proteomics approach of difference gel electrophoresis, we have identified an immunophilin FKBP52 (FK506 binding protein 4) as one of the Hoxa10-mediated signaling molecules in the uterus [10].
• To determine if Hoxa10 mediates the developmental effects of progesterone in the endometrial cell compartments, we performed in vivo uterine transfection using pcDNA3.1/Hoxa10 in estrogen-primed, ovariectomized mice and compared results to mice treated with progesterone [11].
• Hoxa10, a homeodomain transcription factor, is dynamically expressed in adult uterine endometrium where it is necessary for embryo implantation [11].

Anatomical context of Hoxa10

• We have examined the effects of simultaneous inactivation of Hoxa10 and Hoxd10 on mouse hindlimb skeletal and nervous system development [12].
• Proteomic analysis identifies immunophilin FK506 binding protein 4 (FKBP52) as a downstream target of Hoxa10 in the periimplantation mouse uterus [10].
• We found that FKBP52, a cochaperone protein known to influence steroid hormone receptor functions, is down-regulated in stromal cells of Hoxa10-/- mice [10].
• Identification of a Hoxd10-regulated transcriptional network and combinatorial interactions with Hoxa10 during spinal cord development [13].
• Hoxa10 and Hoxd10 coordinately regulate lumbar motor neuron patterning [14].

Associations of Hoxa10 with chemical compounds

• Hoxa10-/- female mice have implantation and decidualization failure due specifically to reduced uterine responsiveness to progesterone and defective stromal cell proliferation during uterine receptivity and implantation [10].
• In vivo MXC blocked the effect of E2 on Hoxa10 expression [15].
• We also demonstrate that DNA/liposome complexes containing the same Hoxa10 constructs that alter fertility in mice, can affect Hoxa10 expression in a human endometrial cell line [3].
• The uteri of Hoxa10(-/-) mice demonstrate progesterone resistance; several genes, including prostaglandin receptors, are inappropriately regulated in response to progesterone [4].

Regulatory relationships of Hoxa10

• Hoxa-10 regulates uterine stromal cell responsiveness to progesterone during implantation and decidualization in the mouse [2].
• Hoxa-10 influences a host of uterine genes and natural killer cell function during appropriate development of regional decidualization at the site of implantation [16]
• Hoxa-10 signaling controls two opposing cell cycle regulators: cyclin D3 (a key factor that promotes cell proliferation) [17] and cyclin G1 (a factor that inhibits cell proliferation) [18] in the uterus during early pregnancy.

Other interactions of Hoxa10

• These observations suggest that Hoxa10 and Hoxd10 coordinately regulate skeletal development and innervation of the hindlimb [12].
• MATERIALS AND METHODS: Hoxa10 and Gnrhr deficient mice were intercrossed with Insl3 transgenic mice [1].
• RESULTS: Transgenic over expression of Insl3 failed to restore normal testicular descent in Hoxa10 or Gnrhr deficient males [1].
• Uterine Msx-1 and Wnt4 signaling becomes aberrant in mice with the loss of leukemia inhibitory factor or Hoxa-10: evidence for a novel cytokine-homeobox-Wnt signaling in implantation [19].
• Expression and gene targeting studies have shown that leukemia inhibitory factor (LIF), a cytokine of the IL-6 family, and Hoxa-10, an abdominalB-like homeobox gene, are crucial to implantation and decidualization in mice [19].

Analytical, diagnostic and therapeutic context of Hoxa10

• Nine genes showed changes in expression of the same sign and similar magnitude using RT-PCR in Hoxd10 single mutant animals, with additional changes in expression seen in Hoxa10/Hoxd10 double mutant animals [13].
• We altered the expression of Hoxa10 in the uterus of cycling adult female mice and examined the uterus at the time of implantation by transmission electron microscopy for alterations in epithelial morphology [20].
• Furthermore, in situ hybridization shows that this region coincides with the anterior limit of embryonic Hoxa-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 [21].

References