Abstract
Purpose of Study: Preterm birth/ low birthweight is the second leading cause of infant mortality. In 2004, 12.5% of all births in the US were preterm. Up to 50% of all preterm births are idiopathic. The incidence of idiopathic preterm labor has not decreased in the last 40 years because the mechanisms that initiate normal labor are poorly understood. In order to understand which myometrial genes are important in labor we compared the genes expressed in the gravid uterus of wildtype mice to the cyclooxygenase-1 (COX-1) knockout mouse, a model of delayed labor.
Methods Used: Mating of estrous wildtype (=4) and COX-1 knockout (=4) females to stud males was confirmed by detection of a copulation plug, designated day 0.5. Plugged females were removed from the male cage to ensure accurate gestational timing. In order to identify genes that are important in parturition, we isolated gravid day 18.0 uterine RNA using Trizol followed by RNeasy. Gene expression levels were compared using the Affymetrix 430 2.0 GeneChip. We have confirmed expression of some of these genes by Northern analysis. We have also localized these genes in the gravid uterus by in situ hybridization.
Summary of Results: We identified 347 genes that were up- or down-regulated at least 1.5-fold in the knockout mice. Of these genes 11 had previously been identified as changing at least 2-fold in the normal gravid mouse uterus between days 13.5 and 16.5 or 19.0. Expression of 4 of these genes affects the immune cascade and expression of 3 other genes affects muscle contractions. In the normal mouse Tnfrsf9 decreases between gestational day 13.5 and 19.0 by 2.6-fold and Tnni 2 decreases 5.9- fold. On gestational day 18.0 Tnfrsf9 is up-regulated 1.5-fold and 2.7- fold and Tnni2 is down-regulated 1.6-fold and 1.7-fold in the knockout mouse by microarray and Northern analysis, respectively. In situ hybridization showed no difference in location of expression between the control and knockout mice. Tnfrsf9 was expressed in immune cells in the decidua. Tnni2 was expressed in the circular layer of the myometrium.
Conclusions: Of the 346 uterine genes we identified as differing between the gravid normal and COX-1 knockout mouse, only 11 genes were also identified as changing after day 13.5 in the normal mouse gravid uterus. The majority of these genes are involved in the immune response or muscle contraction suggesting that both processes are important in the normal timing of parturition.
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Zhao, B., Koon, D., Curtis, A. et al. 20 Abnormal Uterine Gene Expression During Pregnancy in a Mouse Model of Delayed Parturition.. Pediatr Res 60, 493 (2006). https://doi.org/10.1203/00006450-200610000-00042
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DOI: https://doi.org/10.1203/00006450-200610000-00042