Normal expression of cyclin D2 is crucial for FSH-mediated ovarian granulosa cell proliferation. Cyclin D2-null female mice are sterile because the growth of the granulosa cells is impaired. In the normal mouse, FSH induces whereas LH inhibits cyclin D2 expression in granulosa cells. The elucidation of the regulatory pathways governing the expression of cyclin D2 will enhance our understanding of the normal development of granulosa cells. Others and we have found that Inducible cAMP Early Repressor (ICER) expression is induced by LH in granulosa cells. We demonstrated that in cultured naive granulosa cells, ICER repressed the activity of the cyclin D2 promoter. ICER was shown to mediate this repression through a putative cAMP response element (CRE) present in the cyclin D2 promoter. Moreover, ectopic expression of ICER in naive granulosa cells completely inhibits PKA-induced DNA synthesis. These data suggest that ICER is involved in the normal development of ovarian granulosa cells by controlling cyclin D2 expression. In order to test this hypothesis we propose to use inducible and granulosa-specific ICER transgenic mice. The following specific aims are proposed: 1) Biochemical validation of the mouse model; an inducible ovarian specific transgenic of ICER; 2) To determine the physiological effects of ICER induction by FSH on granulosa cells; 3) To determine whether ICER regulates cyclin D2 expression in vivo. The goal of this proposal is to complete the characterization of these mice and to obtain the necessary preliminary data to use these mice as a model system to study ICER regulation of ovarian development. The data generated in this proposal will form the basis for a future R01 application. ? ?
| Muñiz, Luis C; Molina, Carlos A (2016) The transcriptional repressor ICER binds to multiple loci throughout the genome. Biochem Biophys Res Commun 478:1462-5 |
| Muniz, Luis C; Yehia, Ghassan; Memin, Elisabeth et al. (2006) Transcriptional regulation of cyclin D2 by the PKA pathway and inducible cAMP early repressor in granulosa cells. Biol Reprod 75:279-88 |
