Cyclin N-terminal domain-containing 1 (CNTD1) is critical for crossover designation during meiotic prophase I and for maintenance of ovarian reserve in mammalian oocytes

Abstract

In meiotic prophase I, hundreds of double-strand breaks (DSBs) are formed throughout the genome. A majority of these breaks are repaired as non-crossovers (NCOs), while a minor subset are repaired as crossovers (CO). COs are essential for the faithful segregation of homologous chromsomes at the end of prophase I and errors in CO designation can result in aneuploidy, germ cell death, birth defects, or infertility. These errors are more evident in female meiosis compared to males and suggests that the events of meiotic prophase I are sexually dimorphic with respect to CO formation, placement, resolution, and/or surveillance. Here, we demonstrate a critical role for Cyclin N-Terminal Domain Containing 1 (CNTD1) protein in ensuring appropriate CO frequency and distribution across the genome during meiosis in females. We find that CNTD1 localizes with the heterodimer, MutL{gamma}, which marks the majority of CO that emerge in pachynema of prophase I, implicating CNTD1 in late-stage CO designation and/or maturation. Accordingly, loss of Cntd1 in oocytes results in failure to load MutL{gamma} and thus results in a catastrophic loss of chiasmata and sterility. Further investigation yielded a distinct phenotype in which the primordial follicles that form upon dictyate arrest are steadily lost from birth onwards, a temporal loss of follicles that is different to that seen in other CO mutants. We find that this follicle loss in Cntd1 mutants is dependent on the checkpoint kinase CHK2. Thus, in females, loss of Cntd1 appears to result in phenotypes that are temporally disconnected from early and late CO mutants such as MutS{gamma} and MutL{gamma}, which show early prophase I disruption and ablation of ovary structure, and no prophase I disruption and an appearance of wildtype ovaries, respectively. These data suggest novel dual roles for CNTD1 in CO designation and faithful progression of oocytes into dictyate arrest at late pachynema, the latter being critical for establishing the ovarian reserve in female mice.