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Title: Altered Gestation Length in Mice Null for the Krüppel-like Factor 9 Gene or Heterozygous for the Leptin Receptor Mutation: Useful Models for Parturition Defects?

Author
item SIMMEN, ROSALIA
item VELARDE, MICHAEL
item ZENG, ZHAOYANG
item SIMMEN, FRANK
item EVSIKOVA, CARALINA

Submitted to: Society for the Study of Reproduction Annual Meeting
Publication Type: Abstract Only
Publication Acceptance Date: 4/15/2007
Publication Date: 7/1/2007
Citation: Simmen, R.C., Velarde, M.C., Zeng, Z., Simmen, F.A., Evsikova, C.D. 2007. Altered gestation length in mice null for the Krüppel-like factor 9 gene or heterozygous for the leptin receptor mutation: Useful models for parturition defects? [abstract]. Biology of Reproduction. 2007 Special Issue:231.

Interpretive Summary: Premature and delayed labor occurs in approximately 8-12% of pregnancies in the United States, resulting in childbirth-related deaths or other medical complications, which translates to significant emotional, social, and economic burdens. Ethical considerations on the use of human tissue samples and the inability to precisely time the date of childbirth in humans lead researchers to utilize animal models for understanding the contribution of the uterus during labor. To study the parameters involved in childbirth, we used two mouse models: a mouse strain without the gene called Krüppel-like factor 9, and another mouse strain with a mutation in the gene called Leptin receptor. Our data indicate that both mice strains may serve as suitable models to study labor-associated defects and we will use these models to help determine the causes of premature and delayed pregnancy, with the idea of eventually preventing these conditions.

Technical Abstract: The etiologies of pre-term and delayed labor are not well-understood and have been ascribed in part to uterine dysfunction. Clinical conditions of premature and delayed labor, with 8-12% frequencies in the United States, result in perinatal mortality and morbidity, with attendant significant emotional, social, and economic burdens. Given the ethical considerations on the use of human tissues and the inability to assess precise temporal changes in human myometrial samples at and close to term, relevant animal models to appraise new paradigms in uterine myometrial biology for further understanding the contribution of myometrial function to normal and abnormal parturition remain paramount. To address this, we characterized two mouse models for gestation lengths: 1) female mice (C57BLK/6J) null for the SP1-family member Kruppel-like Factor 9 (KLF9) which we previously reported to exhibit reduced uterine progesterone sensitivity and sub-fertility; and 2) female mice (BKS/KsJ) heterozygous for the Leptin receptor mutation (+/db.BKS) and which often display maternal gestational diabetes (MGD). Matings of Klf9 WT females to Klf9 knockout (KO) males and conversely, KO females to WT males to generate heterozygote pups and eliminate the contribution of fetal genotype, resulted in 82% (n=11) of WT dams delivering at dpc19.5 in contrast to 'dpc20.5 for 70% of KO dams (n=20) (P=0.009). Serum P levels did not differ for WT and KO mice at late pregnancy (dpc17.5, dpc18.5) and parturition. Moreover, while 10.6% of KO dams were observed to exhibit labor complications, only 1% of pregnancies were problematic for WT counterparts (P=0.014). The incidence of neonatal death in WT (6.1%) and KO (25.0%) dams also differed (P=0.016). Hormone-primed (5 IU eCG/5 IU hCG) +/db.BKS (n=4) and +/+.BKS (n=4) females were mated overnight to +/+.BKS and +/db.BKS males, respectively to yield litters composed of 50% heterozygous and 50% wildtype pups to circumvent possible confounding effects of litter genotype during the pregnancy. Compared to +/+.BKS dams, +/db.BKS dams have a shorter gestational length (median 19 vs 21 days, P<0.02), although no differences were detected in the median litter size (P>0.55). At mid-gestation, +/db.BKS dams have elevated circulating glucose levels compared to +/+.BKS dams (164.0 ± 12.9 mg/dL vs. 76.0 ± 6.2 mg/dL, P<0.0014). Preliminary analyses for Klf9 transcript levels in myometrium samples of these two genotypes at parturition using quantitative real-time PCR indicated numerically higher Klf9 expression in +/db.BKS than in +/+.BKS counterparts. Results suggest that Klf9 null and +/db.BKS mice may constitute suitable models to investigate pathophysiology underlying parturition defects and the contribution of KLF9 to these conditions.