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.
The behavior of meiotic chromosomes differs in several respects from that of their mitotic counterparts, resulting in the generation of genetically distinct haploid cells. This has been attributed in part to a meiosisspecific chromatin-associated protein structure, the synaptonemal complex. This complex consist of two parallel axial elements, each one associated with a pair of sister chromatids, and a transverse filament located between the synapsed homologous chromosomes. Recently, a different protein structure, the cohesin complex, was shown to be associated with meiotic chromosomes and to be required for chromosome segregation. To explore the functions of the two different protein structures, the synaptonemal complex and the cohesin complex, in mammalian male meiotic cells, we have analyzed how absence of the axial element affects early meiotic chromosome behavior. We find that the synaptonemal complex protein 3 (SCP3) is a main determinant of axial-element assembly and is required for attachment of this structure to meiotic chromosomes, whereas SCP2 helps shape the in vivo structure of the axial element. We also show that formation of a cohesincontaining chromosomal core in meiotic nuclei does not require SCP3 or SCP2. Our results also suggest that the cohesin core recruits recombination proteins and promotes synapsis between homologous chromosomes in the absence of an axial element. A model for early meiotic chromosome pairing and synapsis is proposed.The eukaryotic cell cycle ensures that chromosomes are correctly replicated and symmetrically divided between daughter cells. Errors in the chromosomal segregation process can generate aneuploid cells, which are either not viable or contribute to cancer development, infertility, or other aspects of human disease. Two different strategies for cell division are active in eukaryotic organisms, mitosis and meiosis. Meiosis differs in several respects from mitosis; for example, meiotic cells undergo two cell divisions (M1 and M2) without an intervening DNA replication step, resulting in the generation of haploid cells. Furthermore, homologous chromosomes (each consisting of two sister chromatids) recombine and synapse in prophase I. The homologs are then separated at anaphase I, while the sister chromatids remain associated until the second meiotic division (33, 54).How can the differences between mitotic and meiotic chromosomal behavior be explained? Our understanding of the mechanisms that regulate chromosome synapsis has increased tremendously over the past few years, and two different protein complexes have been shown to take part in these processes, the cohesin complex and the synaptonemal complex (SC) (25,45). We now know that sister chromatids in mitotic cells remain associated by protein complexes called cohesins (14, 26), which consist of at least four different subunits (SMC1, SMC3, SCC1, and SCC3). SMC1 and SMC3 have been shown to bind DNA in vitro (2, 3). Cohesin complexes become attached to chromosomes in somatic cells in the G 1 phase and are deposite...
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