Gene Expression Profiling Reveals Putative HOXA10 Downstream Targets in the Periimplantation Mouse Uterus

Abstract

HOXA10 encodes a transcription factor required for endometrial receptivity and embryo implantation. The objective of this study was to identify and to characterize those molecular markers regulated by HOXA10 expression. The authors have identified putative HOXA10 target genes identified by microarray analysis employing a murine model of transient HOXA10 expression during the anticipated implantation window. Microarray analysis identified 40 statistically significant genes regulated by HOXA10 overexpression of which 31 genes were downregulated greater than 2-fold over control and 9 genes were upregulated. Cellular ontogenies of differentially expressed genes include cell adhesion molecules, signal transduction factors, and metabolic regulators. Semiquantitative real-time reverse transcriptase polymerase chain reaction confirmed regulation of selected candidate genes. Examples included clusterin (Clu), phoshoglycerate 3-dehydrogenase (3-Pgdh), and tumor-associated calcium signal transducer 2 (Tacstd2). Elucidation of these pathways will allow further characterization of the molecular mechanisms governing endometrial development, which also may function to enhance uterine receptivity. KeywordsImplantation; HOXA10; 3-phosphoglycerate dehydrogenase; microarray; endometrium The ability of the blastocyst to implant into a receptive endometrium governs reproductive success. Acute changes within this environment are driven by molecular events essential to the implantation process. Thus, the cascade of signaling events that occur in both fetal and maternal tissues at the time of implantation establishes an appropriate milieu critical to the development and survival of the fetus. Defects in the formation of this network and the inability to sustain this cross talk are believed to result in various pregnancy-associated complications that may manifest throughout the pregnancy. 1,2The homeobox (HOX) genes encode transcription factors that guide embryologic development as well as regulate differential gene expression within the endometrium with each menstrual cycle. 3 These regulators, first associated with directing axial patterning 4 through activation and repression of downstream targets, since have been demonstrated to be conserved across species and are essential to metazoan existence. [5][6][7] Although there are no known human mutations in HOXA10, women with decreased secretory phase HOXA10 expression have lower implantation rates. 13 Animal models generated to harbor selected gene knockouts demonstrate infertility phenotypes and continue to provide insight into the potential biomarkers that are involved in regulating the molecular implantation window. In particular, targeted disruption of the HOXA10 gene in mice results in a transformation of the upper uterine segment into an oviduct-like structure and inhibits implantation, even when embryos are transferred to the grossly unaffected lower uterine segment. 13,14 HOXA10-null mice produce normal numbers of embryos that are able to implant in wild-type surrogate ...

HOXA10 regulates endometrial GABAAπ receptor expression and membrane translocation

“…They are both regulated and/or modulated by the sex steroid progesterone (45). A recent microarray-based study from our laboratory identified the GABA A subunit as a potential Hoxa10 target gene in the murine endometrium (45). Here we demonstrate that not only was GABA A subunit gene expression regulated by HOXA10, its membrane translocation was as well.…”

“…Both HOXA10 and GABA A subunit receptors are expressed in the endometrium at the time of embryonic implantation (21). They are both regulated and/or modulated by the sex steroid progesterone (45). A recent microarray-based study from our laboratory identified the GABA A subunit as a potential Hoxa10 target gene in the murine endometrium (45).…”

FOXO1 Expression and Regulation in Endometrial Tissue during the Menstrual Cycle and in Early Pregnancy Decidua

“…Some of these implicated genes include: urocortin [18], IL-15 [19], HOXA10 (homeobox A10) [20], and leukemia inhibitory factor [21]. It is plausible then that FOXO1 may be included with urocortin, IL-15, HOXA10, and leukemia inhibitory factor as a contributor to the progression of stromal cell decidualization.…”

Regulation of tryptophan 2,3-dioxygenase by HOXA10 enhances embryo viability through serotonin signaling

“…Endometrial ␤ 3 -integrin subunit gene expression is directly upregulated by HOXA10 (13). cDNA microarray has recently been used to broadly search for potential downstream targets of HOXA10 (24,45). When HOXA10 was overexpressed, several target genes were found to have significantly increased expression.…”

“…When HOXA10 was overexpressed, several target genes were found to have significantly increased expression. Of these, the largest increase was in the tryptophan 2,3-dioxygenase (TDO) gene that increased eightfold in response to constitutive expression of HOXA10 (45).…”