CCAAT/Enhancer-Binding Proteins α and β Regulate Ovulation and Gene Expression via Dose- and Stage-Dependent Mechanisms.

Abstract

The preovulatory luteinizing hormone (LH) surge orchestrates complex cellular and molecular events leading to ovulation. CCAAT/enhancer-binding proteins α and β (C/EBPα/β) are transcription factors acutely induced by the LH surge and crucial for ovulation and granulosa cell luteinization. However, biological processes (BPs) and their regulatory mechanisms downstream of C/EBPα/β in the preovulatory ovary are not completely understood. To address this knowledge gap, we generated Cebpa/bfl/fl;Pgr-Cre mutants and compared them with Cebpa/bfl/fl;Cyp19a1-Cre mutant female mice: Cebpa/bfl/fl;Cyp19a1-Cre mutants have undetectable levels of C/EBPα/β throughout the preovulatory stages and do not ovulate, aligning with previous reports; and Cebpa/bfl/fl;Pgr-Cre mutants present gradual depletion of C/EBPα/β during the late preovulatory stage and a reduced ovulation rate. Comparison of these two models indicates that sustained expression of C/EBPα/β throughout the preovulatory stages is necessary for successful ovulation and provides a unique opportunity to interrogate gene regulatory mechanisms by C/EBPα/β during different preovulatory time windows and the effect of dysregulating C/EBPα/β on ovulation-associated BPs. Our study revealed that C/EBPα/β regulate gene expression and distinct biological functions such as vascular remodeling via dose- and preovulatory stage-dependent mechanisms. These findings shed new light on the intricate mechanisms of gene regulation by C/EBPα/β downstream of the LH surge.