Abstract
Core Binding Factors (CBFs) are a small group of heterodimeric transcription factor complexes composed of DNA binding proteins, RUNXs, and a non-DNA binding protein, CBFB. The LH surge increases the expression of Runx1 and Runx2 in ovulatory follicles, while Cbfb is constitutively expressed. To investigate the physiological significance of CBFs, we generated a conditional mutant mouse model in which granulosa cell expression of Runx2 and Cbfb was deleted by the Esr2Cre. Female Cbfbflox/flox;Esr2cre/+;Runx2flox/flox mice were infertile; follicles developed to the preovulatory follicle stage but failed to ovulate. RNA-seq analysis of mutant mouse ovaries collected at 11 h post-hCG unveiled numerous CBFs-downstream genes that are associated with inflammation, matrix remodeling, wnt signaling, and steroid metabolism. Mutant mice also failed to develop corpora lutea, as evident by the lack of luteal marker gene expression, marked reduction of vascularization, and excessive apoptotic staining in unruptured poorly luteinized follicles, consistent with dramatic reduction of progesterone by 24 h after hCG administration. The present study provides in vivo evidence that CBFs act as essential transcriptional regulators of both ovulation and luteinization by regulating the expression of key genes that are involved in inflammation, matrix remodeling, cell differentiation, vascularization, and steroid metabolisms in mice.
Highlights
Core Binding Factors (CBFs) are a small group of heterodimeric transcription factor complexes composed of DNA binding proteins, RUNXs, and a non-DNA binding protein, CBFB
To generate a mutant mouse line bearing granulosa cell deletion of both the Runx[2] and Cbfb gene (Cbfbflox/flox;Esr2Cre/+;Runx2flox/flox, referred as gcCbfb;Runx2KO), the breeding scheme depicted in Fig. 1A was used by first mating female Runx2flox/flox with male Cbfbflox/flox;Esr2Cre/+ mice
These data confirmed the deletion of Runx[2] and Cbfb as well as the loss of RUNX1 protein in granulosa cells of preovulatory follicles in mutant mice
Summary
Core Binding Factors (CBFs) are a small group of heterodimeric transcription factor complexes composed of DNA binding proteins, RUNXs, and a non-DNA binding protein, CBFB. Cbfbflox/flox;Esr2Cre/+ mice showed only ~65% reduction in ovulation rates, and the majority of unruptured antral follicles transformed into morphologically normal-looking CL, progesterone levels were reduced on day 3 post-hCG administration compared to those in wild-type animals[10]. Consistent with these changes, the expression of two ovulatory genes (Edn[2] and Ptgs1) and several luteal genes (Lhcgr, Sfrp[4], Wnt[4], Ccrl[2], Lipg, Saa[3], and Ptgfr) was compromised in these mutant mouse lines[9,10]. These data indicated that the deletion of Cbfb in granulosa cells resulted in a partial reduction of ovulation rate and CL function in mice
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