During meiosis, the homologous chromosomes pair and recombine. An evolutionarily conserved protein structure, the synaptonemal complex (SC), is located along the paired meiotic chromosomes. We have studied the function of a structural component in the axial/lateral element of the SC, the synaptonemal complex protein 3 (SCP3). A null mutation in the SCP3 gene was generated, and we noted that homozygous mutant males were sterile due to massive apoptotic cell death during meiotic prophase. The SCP3-deficient male mice failed to form axial/lateral elements and SCs, and the chromosomes in the mutant spermatocytes did not synapse. While the absence of SCP3 affected the nuclear distribution of DNA repair and recombination proteins (Rad51 and RPA), as well as synaptonemal complex protein 1 (SCP1), a residual chromatin organization remained in the mutant meiotic cells.

Crossing-over ensures accurate chromosome segregation during meiosis, and every pair of chromosomes obtains at least one crossover, even though the majority of recombination sites yield non-crossovers. A putative regulator of crossing-over is RNF212, which is associated with variation in crossover rates in humans. We show that mouse RNF212 is essential for crossing-over, functioning to couple chromosome synapsis to the formation of crossover-specific recombination complexes. Selective localization of RNF212 to a subset of recombination sites is shown to be a key early step in the crossover designation process. RNF212 acts at these sites to stabilize meiosis-specific recombination factors, including the MutSγ complex (MSH4-MSH5). We infer that selective stabilization of key recombination proteins is a fundamental feature of meiotic crossover control. Haploinsufficiency indicates that RNF212 is a limiting factor for crossover control and raises the possibility that human alleles may alter the amount or stability of RNF212 and be risk factors for aneuploid conditions.

The data indicate that cohesin declines gradually during the long prophase arrest that precedes MI in female mammals. In aged oocytes, cohesin levels fall below the level required to stabilize chiasmata and to hold sister centromeres tightly together, leading to chromosome missegregation during MI. Cohesin loss may be amplified by a concomitant decline in the levels of the centromeric cohesin protector Sgo2. These findings indicate that cohesin is a key molecular link between female aging and chromosome missegregation during MI.

Ubiquitin-mediated proteolysis is the key to cell cycle control. Anaphase-promoting complex/cyclosome (APC) is a ubiquitin ligase that targets cyclin B and factors regulating sister chromatid separation for proteolysis by the proteasome and, consequently, regulates metaphase-anaphase transition and exit from mitosis. Here we report that Cdc2-cyclin B-activated Polo-like kinase (Plk) specifically phosphorylates at least three components of APC and activates APC to ubiquitinate cyclin B in the in vitro-reconstituted system. Conversely, protein kinase A (PKA) phosphorylates two subunits of APC but suppresses APC activity. PKA is superior to Plk in its regulation of APC, and Plk activity peaks whereas PKA activity is falling at metaphase. These results indicate that Plk and PKA regulate mitosis progression by controlling APC activity.

Aneuploidy (trisomy or monosomy) is the leading genetic cause of pregnancy loss in humans and results from errors in meiotic chromosome segregation. Here, we show that the absence of synaptonemal complex protein 3 (SCP3) promotes aneuploidy in murine oocytes by inducing defective meiotic chromosome segregation. The abnormal oocyte karyotype is inherited by embryos, which die in utero at an early stage of development. In addition, embryo death in SCP3-deficient females increases with advancing maternal age. We found that SCP3 is required for chiasmata formation and for the structural integrity of meiotic chromosomes, suggesting that altered chromosomal structure triggers nondisjunction. SCP3 is thus linked to inherited aneuploidy in female germ cells and provides a model system for studying age-dependent degeneration in oocytes.