Sexual dimorphic regulation of recombination by the synaptonemal complex in C. elegans
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eLife assessment
This important study shows the sexually dimorphic dynamics of the components of meiosis-specific chromosome structure and the gene-dosage effect of the components on meiotic recombination. The experimental evidence in the paper is solid with cytological analysis with Fluorescence Recovery After Photobleaching (FRAP). The work will be of interest to researchers working on meiosis and chromosome dynamics.
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Abstract
In sexually reproducing organisms, germ cells faithfully transmit the genome to the next generation by forming haploid gametes, such as eggs and sperm. Although most meiotic proteins are conserved between eggs and sperm, many aspects of meiosis are sexually dimorphic, including the regulation of recombination. The synaptonemal complex (SC), a large ladder-like structure that forms between homologous chromosomes, is essential for regulating meiotic chromosome organization and promoting recombination. To assess whether sex-specific differences in the SC underpin sexually dimorphic aspects of meiosis, we examined Caenorhabditis elegans SC central region proteins (known as SYP proteins) in oogenesis and spermatogenesis and uncovered sex-specific roles for the SYPs in regulating meiotic recombination. We find that SC composition, specifically SYP-2, SYP-3, SYP-5, and SYP-6, is regulated by sex-specific mechanisms throughout meiotic prophase I. During pachytene, both oocytes and spermatocytes differentially regulate the stability of SYP-2 and SYP-3 within an assembled SC. Further, we uncover that the relative amount of SYP-2 and SYP-3 within the SC is independently regulated in both a sex-specific and a recombination-dependent manner. Specifically, we find that SYP-2 regulates the early steps of recombination in both sexes, while SYP-3 controls the timing and positioning of crossover recombination events across the genomic landscape in only oocytes. Finally, we find that SYP-2 and SYP-3 dosage can influence the composition of the other SYPs in the SC via sex-specific mechanisms during pachytene. Taken together, we demonstrate dosage-dependent regulation of individual SC components with sex-specific functions in recombination. These sexual dimorphic features of the SC provide insights into how spermatogenesis and oogenesis adapted similar chromosome structures to differentially regulate and execute recombination.
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eLife assessment
This important study shows the sexually dimorphic dynamics of the components of meiosis-specific chromosome structure and the gene-dosage effect of the components on meiotic recombination. The experimental evidence in the paper is solid with cytological analysis with Fluorescence Recovery After Photobleaching (FRAP). The work will be of interest to researchers working on meiosis and chromosome dynamics.
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Reviewer #1 (Public Review):
The synaptonemal complex (SC) is a meiosis-specific tripartite chromosome structure for chromosome synapsis and regulates crossover formation essential for proper chromosome segregation during meiosis. In this interesting paper, the authors studied the dynamic behavior of two components of SC central regions, SYP-2 and SYP-3, in both oocytes and spermatocytes in C. elegans and also the effect of the dosage of the proteins on meiotic recombination and found sex-dimorphic and/or SYP-2/3 dosage sensitive dynamics of the SC components and proteins involved in crossover formation on the meiotic chromosomes, suggesting the intimate relationship between SC central regions and meiotic recombination.
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Reviewer #2 (Public Review):
The synaptonemal complex (SC) is a ladder-like structure that is assembled between homologous chromosomes during meiotic prophase I. This structure is critical for accurate chromosome segregation as it is required for both crossover formation and regulating crossover frequency. In this study, the composition of the SC throughout meiotic prophase, SC dynamics, and its contribution to crossover formation is compared between male meiosis and female meiosis using C. elegans. Although the SC is found in both sexes, many aspects of meiosis, including recombination initiation and formation, differ between sexes. Whether sex-specific differences extend to the SC and how this influences recombination events has not been investigated. The authors use fluorescently-tagged SC central region proteins (SYP-2 and SYP-3) to …
Reviewer #2 (Public Review):
The synaptonemal complex (SC) is a ladder-like structure that is assembled between homologous chromosomes during meiotic prophase I. This structure is critical for accurate chromosome segregation as it is required for both crossover formation and regulating crossover frequency. In this study, the composition of the SC throughout meiotic prophase, SC dynamics, and its contribution to crossover formation is compared between male meiosis and female meiosis using C. elegans. Although the SC is found in both sexes, many aspects of meiosis, including recombination initiation and formation, differ between sexes. Whether sex-specific differences extend to the SC and how this influences recombination events has not been investigated. The authors use fluorescently-tagged SC central region proteins (SYP-2 and SYP-3) to quantify the amount of SC protein accumulation per nucleus. The data indicate that the composition of the SC is dynamic throughout the meiotic prophase with sexually dimorphic properties. In addition, by examining and quantifying the number of proteins that mark different recombination intermediates, the authors found that not only does the SC regulate different aspects of recombination, but the regulation is sex-specific. Overall, the assays and quantification in this manuscript are of high quality.
Overall, the manuscript is largely descriptive and doesn't test possible mechanisms behind the observed sex-specific differences. However, this study is of high interest as these sexually dimorphic phenotypes have not been previously studied. The data presented in this paper set a nice foundation for future work. The manuscript is mostly well-written and the data is presented well but lacks explanations for some of the observed phenotypes. Some minor textual revisions would provide insights into some of the male-specific phenotypes that were noted without explanation (e.g. Why might SYP-3 be more dynamic in early pachytene in spermatocytes?). In addition, the introduction could be revised to provide a more coherent flow and to highlight the significance of sexual dimorphic aspects of meiosis.
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Reviewer #3 (Public Review):
Cahoon set out to demonstrate that sexual dimorphic outcomes of meiosis are caused by different regulations of the synaptonemal complex (SC). In the employed model organism C. elegans it has been shown that the SC consists of at least 6 different proteins (SYP-1-6) and that their assembly into this intricate structure is mutually dependent and that crossover formation is drastically, if not completely abolished, in the absence of individual SC mutants (SYP-5 and SYP-6 are functionally redundant).
The authors employ FRAP analysis and examine the rate of reincorporation of the synapsis components SYP-2 and SYP3 in three different regions of the gonad and compare the incorporation after photobleaching in hermaphrodite and male gonads. They find that SYP-2 dynamics is increased in spermatocytes, whereas in …
Reviewer #3 (Public Review):
Cahoon set out to demonstrate that sexual dimorphic outcomes of meiosis are caused by different regulations of the synaptonemal complex (SC). In the employed model organism C. elegans it has been shown that the SC consists of at least 6 different proteins (SYP-1-6) and that their assembly into this intricate structure is mutually dependent and that crossover formation is drastically, if not completely abolished, in the absence of individual SC mutants (SYP-5 and SYP-6 are functionally redundant).
The authors employ FRAP analysis and examine the rate of reincorporation of the synapsis components SYP-2 and SYP3 in three different regions of the gonad and compare the incorporation after photobleaching in hermaphrodite and male gonads. They find that SYP-2 dynamics is increased in spermatocytes, whereas in oocytes SYP-3 dynamics is increased. They also found differing profiles of incorporation during the progression of prophase I for those two synapsis components in the two sexes.
Furthermore, the authors show that syp-2/+ and syp-3/+ show signs of haploinsufficiency, as demonstrated by increased embryonic lethality and the missegregation of the X chromosome. In these mutants, the authors examined the kinetics of the appearance of recombination foci, where they used RAD-51 as a measure for progress of homologous recombination and repair pathway choice (repair via the sister versus the homolog and/or non-homologous end joining), MSH-5 for stabilisation of the strand invasion product and COSA-1 as a marker for crossover designation.
The authors show that in the hypomorphs the behaviour of some recombination markers change. The counts of the numbers of COSA-1 are not explaining the missegregation of the X chromosome. The localisation of the crossovers shifts towards the pairing centre chromosome ends in the hypomorphs.The manuscript is descriptive and the link that dimorphic incorporation rates of SYP-2 and SYP-3 are causative for recombination dimorphisms is not substantiated by the shown experiments. The observed phenomena in the heterozygous syp mutants could be due to general SC defects and not the lack of a critical amount at a specific point during recombination. Overall, the FRAP experiments do not address the possible different synthesis rates of the employed markers (it would be more meaningful to examine the incorporation under protein synthesis inhibitory conditions) or use a photoconvertible tag, that allows the assessment of new synthesis. It has been well documented that in the more distal regions of the gonad gene expression is upregulated. It is not clear what the contribution of differing gene expression of the examined synapsis proteins to the different dynamic behaviour actually is.
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