Abstract
Recent studies in simple model organisms have shown that centromere pairing is important for ensuring high-fidelity meiotic chromosome segregation. However, this process and the mechanisms regulating it in higher eukaryotes are unknown. Here we present the first detailed study of meiotic centromere pairing in mouse spermatogenesis and link it with key events of the G2/metaphase I transition. In mouse we observed no evidence of the persistent coupling of centromeres that has been observed in several model organisms. We do however find that telomeres associate in non-homologous pairs or small groups in B type spermatogonia and pre-leptotene spermatocytes, and this association is disrupted by deletion of the synaptonemal complex component SYCP3. Intriguingly, we found that, in mid prophase, chromosome synapsis is not initiated at centromeres, and centromeric regions are the last to pair in the zygotene-pachytene transition. In late prophase, we first identified the proteins that reside at paired centromeres. We found that components of the central and lateral element and transverse filaments of the synaptonemal complex are retained at paired centromeres after disassembly of the synaptonemal complex along diplotene chromosome arms. The absence of SYCP1 prevents centromere pairing in knockout mouse spermatocytes. The localization dynamics of SYCP1 and SYCP3 suggest that they play different roles in promoting homologous centromere pairing. SYCP1 remains only at paired centromeres coincident with the time at which some kinetochore proteins begin loading at centromeres, consistent with a role in assembly of meiosis-specific kinetochores. After removal of SYCP1 from centromeres, SYCP3 then accumulates at paired centromeres where it may promote bi-orientation of homologous centromeres. We propose that, in addition to their roles as synaptonemal complex components, SYCP1 and SYCP3 act at the centromeres to promote the establishment and/or maintenance of centromere pairing and, by doing so, improve the segregation fidelity of mammalian meiotic chromosomes.
Highlights
During the first meiotic division, homologous chromosomes pair, recombine and dissociate
We find that SYCP1 and SYCP3 proteins remain at centromeres co-incident with the time of outer kinetochore assembly, and appear to promote steps in the establishment and/or maintenance of centromere pairing until the centromeres begin their attachment to the meiotic spindle
We have characterized events of centromere pairing in male mouse meiosis by analyzing the kinetics of centromere pairing in cells at different stages of prophase in meiosis I
Summary
During the first meiotic division, homologous chromosomes pair, recombine and dissociate. Successful completion of these processes is required for a pair of homologous chromosomes (bivalent) to mount the meiotic spindle. Organization of the chromosomes into pairs ensures orderly segregation of homologous chromosomes to opposite spindle poles at the first meiotic division, ensuring that each gamete receives one copy of each chromosome. Errors in meiotic homologous chromosome segregation are the leading cause of human aneuploidy. Some examples of hereditary diseases caused by aneuploidies are several types of Ataxias and Down, Klinefelter, Edwards and Turner Syndromes [1]. The molecular basis of aneuploidy in humans is poorly understood. Identification and description of mechanisms used to promote meiotic fidelity are essential to improve this understanding
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