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Homeostatic control of recombination is implemented progressively in mouse meiosis

Nature Cell Biology volume 14, pages 424–430 (2012)Cite this article

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Abstract

Humans suffer from high rates of fetal aneuploidy, often arising from the absence of meiotic crossover recombination between homologous chromosomes1. Meiotic recombination is initiated by double-strand breaks (DSBs) generated by the SPO11 transesterase2. In yeast and worms, at least one buffering mechanism, crossover homeostasis, maintains crossover numbers despite variation in DSB numbers3,4,5,6,7,8. We show here that mammals exhibit progressive homeostatic control of recombination. In wild-type mouse spermatocytes, focus numbers for early recombination proteins (RAD51, DMC1) were highly variable from cell to cell, whereas foci of the crossover marker MLH1 showed little variability. Furthermore, mice with greater or fewer copies of the Spo11 gene—with correspondingly greater or fewer numbers of early recombination foci—exhibited relatively invariant crossover numbers. Homeostatic control is enforced during at least two stages, after the formation of early recombination intermediates and later while these intermediates mature towards crossovers. Thus, variability within the mammalian meiotic program is robustly managed by homeostatic mechanisms to control crossover formation, probably to suppress aneuploidy. Meiotic recombination exemplifies how order can be progressively implemented in a self-organizing system despite natural cell-to-cell disparities in the underlying biochemical processes.

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Figure 1: Cell-to-cell variability in numbers of recombination intermediates decreases as meiotic prophase progresses.
Figure 2: Spo11 locus number modulates early recombination indicators but not crossover numbers.
Figure 3: Changes in numbers of recombination-associated foci as meiosis progresses.
Figure 4: Cytological interference is unchanged despite decreased or increased early recombination intermediates.

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Acknowledgements

We thank present and past members of the Jasin and Keeney laboratories for helpful discussions. F.C. was supported by a Ruth L. Kirschstein NRSA (F32HD51392). S.K. is an Investigator of the Howard Hughes Medical Institute. This work was supported by NIH grant HD040916 (to M.J. and S.K.).

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Authors and Affiliations

  1. Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA

    Francesca Cole, Raymond Wang & Maria Jasin

  2. Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA

    Liisa Kauppi, Julian Lange, Ignasi Roig & Scott Keeney

  3. Department of Cell Biology, Cytology and Histology Unit, Physiology, and Immunology, Universitat Autonoma de Barcelona, Barcelona, Spain

    Ignasi Roig

  4. Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA

    Scott Keeney

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  1. Francesca Cole
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Contributions

F.C., S.K. and M.J. designed the experiments. F.C., L.K., J.L., I.R. and R.W. carried out experiments. F.C., S.K. and M.J. wrote the paper.

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Correspondence to Scott Keeney or Maria Jasin.

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Cole, F., Kauppi, L., Lange, J. et al. Homeostatic control of recombination is implemented progressively in mouse meiosis. Nat Cell Biol 14, 424–430 (2012). https://doi.org/10.1038/ncb2451

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