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Delayed Parturition and Altered Myometrial Progesterone Receptor Isoform A Expression in Mice Null for Krüppel-Like Factor 9¹

Department of Physiology and Biophysics,⁵ University of Arkansas for Medical Sciences, and Arkansas Children's Nutrition Center,⁶ Little Rock, Arkansas 72202

ABSTRACT

Preterm and delayed labor conditions are devastating health problems with currently unknown etiologies. We previously showed that the transcription factor Krüppel-like factor 9 (KLF9) influences the expression and/or transcriptional activity of receptors for estrogen and progesterone in endometrial cells in vivo and in vitro. Given that estrogen and progesterone differentially regulate uterine myometrial contractility during gestation, we hypothesized that lack of KLF9 could compromise myometrial function, leading to defects in parturition. To test this, we used mice null for Klf9 to evaluate gestation length, response to the progesterone receptor (PGR) antagonist RU486, expression levels of steroid receptor proteins, nuclear receptor coactivator and contractility-associated genes, and nuclear factor-kappaB (NF-kappaB) DNA binding activity in myometrium near term. Klf9 knockout (KO) mice exhibited delayed parturition by 1–2 days relative to wild-type (WT) counterparts, in the absence of fetal genotype contribution and differences in serum estrogen and progesterone levels. Knockout mice near term were refractory to the abortive action of RU486, and they displayed aberrant myometrial expression patterns of nuclear PGR-A and NF-kappaB p65/RELA relative to WT mice. Myometrial expression levels of nuclear estrogen receptor-alpha did not differ, whereas those for Oxtr and Crebbp mRNAs were lower, in KO versus WT mice. Results indicate that KLF9 contributes to the regulation of PGR-associated components in the myometrium necessary for timely onset of parturition in mice. The present study highlights the potential utility of Klf9 null mice to investigate the pathophysiology of parturition defects involving PGR signaling.

female reproductive tract, myometrium, parturition, progesterone, steroid hormone receptors

³Current address: Department of Obstetrics/Gynecology and Reproductive Sciences, University of California at San Francisco, San Francisco, CA 94143

⁴These authors contributed equally to this work.

¹Supported by National Institutes of Health grant HD21961 and the Arkansas Children's Hospital Research Institute Intramural Grant Program.

Correspondence: ²Rosalia C.M. Simmen, University of Arkansas for Medical Sciences and Arkansas Children's Nutrition Center, 1212 Marshall St., Little Rock, AR 72202. FAX: 501 364 3161; e-mail: simmenrosalia{at}uams.edu