GSE158773
CNOT6/6L-mediated mRNA Degradation in Ovarian Granulosa Cells is a Key Mechanism of Gonadotropin-triggered Follicle Development
CCR4-NOT deadenylase is a major regulator of mRNA turnover in eukaryotes. It contains 2 heterogeneous catalytic subunits encoded by Cnot7/8 and Cnot6/6l genes in vertebrates, respectively. The physiological function of each catalytic subunit was unclear due to potential gene redundancy in vivo. In this study Cnot6/6l double knockout mice were generated. These mice were viable and generally healthy, but females were infertile with irregular estrus cycle and poor ovarian responses to gonadotropins. Follicle-stimulating hormone (FSH) stimulated transcription and translation of mRNAs encoding CNOT6 and CNOT6L in ovarian granulosa cells through the activity of phosphoinositide 3-kinase signaling pathway. Results of transcriptome analyses indicated that FSH downregulated a large number of transcripts in granulosa cells during the transition from pre-antral to antral follicles in a CNOT6/6L-dependent manner. These two deadenylases functioned as key effectors of FSH in altering the developmental programs in granulosa cells and triggered clearance of specific transcripts in growing follicles, particularly those encoding repressing factors of granulosa cell proliferation and steroidogenesis. These results demonstrated that FSH modulates granulosa cells function by stimulating selective translational activation and degradation of existed mRNAs, in additional to inducing de novo gene transcription. Meanwhile, this study provides in vivo evidence that CCR4-NOTCNOT6/6L-mediated mRNA deadenylation is dispensable in most somatic cell types, but is essential for the female reproductive endocrine regulation. Overall design: Examination of WT and CNOT6/6L-null transcriptome in Ovarian Granulosa Cells.