The Reproductive Phenotype of Mice Null for Transcription Factor Krüppel-Like Factor 13 Suggests Compensatory Function of Family Member Krüppel-Like Factor 9 in the Peri-Implantation Uterus1

Abstract

The ovarian hormones estrogen and progesterone promote uterine receptivity and successful pregnancy through their cognate receptors functioning in concert with context-dependent nuclear coregulators. Previously, we showed that the transcription factor Krüppel-like factor (KLF) 9 is a progesterone receptor (PGR) coactivator in the uterus and that mice null for Klf9 exhibit subfertility and reduced progesterone sensitivity. The highly related family member KLF13 displays increased expression in uteri of pregnant and nonpregnant Klf9 null mice and similarly regulates PGR-mediated transactivation in endometrial stromal cells. However, a uterine phenotype with loss of Klf13 has not been reported. In the present study, we demonstrate that Klf13 deficiency in mice did not compromise female fertility and pregnancy outcome. Klf13 null females had litter sizes, numbers of implanting embryos, uterine morphology, and ovarian steroid hormone production comparable to those of wild-type (WT) counterparts. Further, pregnant WT and Klf13 null females at Day Postcoitum (DPC) 3.5 had similar uterine Pgr, estrogen receptor, and Wnt-signaling component transcript levels. Nuclear levels of KLF9 were higher in Klf13 null than in WT uteri at DPC 3.5, albeit whole-tissue KLF9 protein and transcript levels did not differ between genotypes. The lack of a similar induction of nuclear KLF9 levels in uteri of virgin Klf13((-/-)) mice relative to WT uteri was associated with lower stromal PGR expression. In differentiating human endometrial stromal cells, coincident KLF9/KLF13 knockdown by small interfering RNA targeting reduced decidualization-associated PRL expression, whereas KLF9 and KLF13 knockdowns alone reduced transcript levels of WNT4 and BMP2, respectively. Results suggest that KLF9 and KLF13 functionally compensate in peri-implantation uterus for pregnancy success.

Molecular determinants of uterine receptivity

“…However, again there is evidence for compensation. Nuclear levels of Klf9 are higher in Klf13 null uteri (Heard et al, 2012). These observations indicate a potential requirement for Klf9 and/or Klf13 in normal uterine function during early pregnancy.…”

Delineating the 15q13.3 microdeletion phenotype: a case series and comprehensive review of the literature

“…20,27 With respect to placenta previa, there are studies of embryo implantation in a null mouse model implicating the 15q13.3 region gene KLF13, as well as KLF9, a related gene located at 9q13. 35 These genes encode members of the Krüppel-like family of transcription factors, which are needed to maintain the proper progesterone sensitivity regulation that is essential for successful embryo implantation. 36 Further study is required to understand the role of KLF13 in human perinatal outcomes.…”

Krüppel-Like Factor 13 Deficiency in Uterine Endometrial Cells Contributes to Defective Steroid Hormone Receptor Signaling but Not Lesion Establishment in a Mouse Model of Endometriosis1

“…Among the 17 members of the Sp/KLF family [24], KLF13 is the most structurally related to KLF9. Similar to KLF9 [25], KLF13 functions as a PGR-B specific co-regulator in human endometrial cells [26] and the loss of its expression in the cycling (nonpregnant) uterus in mice resulted in diminished PGR-B expression [27]. Surprisingly, unlike Klf9 knock-out female mice which are sub-fertile [14], female mice null for Klf13 exhibit no reproductive phenotype, demonstrating litter sizes, numbers of implanting embryos, uterine morphology and ovarian steroid hormone production comparable to those of wild-type counterparts [27].…”

“…Similar to KLF9 [25], KLF13 functions as a PGR-B specific co-regulator in human endometrial cells [26] and the loss of its expression in the cycling (nonpregnant) uterus in mice resulted in diminished PGR-B expression [27]. Surprisingly, unlike Klf9 knock-out female mice which are sub-fertile [14], female mice null for Klf13 exhibit no reproductive phenotype, demonstrating litter sizes, numbers of implanting embryos, uterine morphology and ovarian steroid hormone production comparable to those of wild-type counterparts [27]. The latter suggests compensatory functions between KLF9 and KLF13; this is supported by our earlier findings of increased KLF13 expression in the peri-implantation endometrium of Klf9 null mice [14] and of KLF9 and KLF13 cross-regulation of the expression…”