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RNF212 is a dosage-sensitive regulator of crossing-over during mammalian meiosis

Nature Genetics volume 45, pages 269–278 (2013)Cite this article

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Abstract

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.

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Figure 1: Dynamic localization of RNF212 to synaptonemal complexes and crossover sites in mouse spermatocytes.
Figure 2: Genetic requirements for RNF212 localization.
Figure 3: Gonad morphology and homolog synapsis in Rnf212−/− knockout mice.
Figure 4: RNF212 is required for chiasma formation and assembly of crossover-specific recombination complexes.
Figure 5: RNF212 stabilizes two ZMM factors, Mutsγ and TEX11.
Figure 6: Rnf212 is haploinsufficient.
Figure 7: Summary and model of RNF212 function.

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Acknowledgements

We thank C. Heyting (Wageningen University) for antibodies to SYCP1 and SYCP3, S. Keeney and M. Jasin (Memorial Sloan-Kettering Cancer Center) for Spo11 knockout mice, M. Paddy for help with SIM imaging, J. Trimmer for help with imaging tissue sections and G. Coop for discussions. Knockout mice were generated in collaboration with the University of California, Davis, Mouse Biology Program (MBP). B.d.M. is supported by grants from the CNRS, Association pour la Recherche sur le Cancer and Agence Nationale de la Recherche (ANR-09-BLAN-0269-01). This work was supported by US National Institutes of Health (NIH) grant R01GM084955 to N.H. N.H. is an Early Career Scientist of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, University of California, Davis, Davis, California, USA

    April Reynolds, Huanyu Qiao, Ye Yang, Jefferson K Chen, Neil Jackson, Kajal Biswas & Neil Hunter

  2. Department of Microbiology & Molecular Genetics, University of California, Davis, Davis, California, USA

    April Reynolds, Huanyu Qiao, Ye Yang, Jefferson K Chen, Neil Jackson, Kajal Biswas & Neil Hunter

  3. Department of Biomedical Sciences, Center for Reproductive Genomics, Cornell University, Ithaca, New York, USA

    J Kim Holloway & Paula E Cohen

  4. Institut de Génétique Humaine, Centre National de Recherche Scientifique (CNRS), Montpellier, France

    Frédéric Baudat & Bernard de Massy

  5. Department of Animal Biology, Center for Animal Transgenesis and Germ Cell Research, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Jeremy Wang

  6. Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden

    Christer Höög

  7. Department of Molecular & Cellular Biology, University of California, Davis, Davis, California, USA

    Neil Hunter

  8. Department of Cell Biology & Human Anatomy, University of California, Davis, Davis, California, USA

    Neil Hunter

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Contributions

A.R., N.J., H.Q., Y.Y., K.B., P.E.C. and N.H. conceived and designed the experiments. A.R., N.J., H.Q., Y.Y., J.K.C., K.B., J.K.H., B.d.M., F.B. and N.H. performed the experiments. A.R., H.Q., Y.Y., J.K.C., K.B., B.d.M. and N.H. analyzed the data. J.W. and C.H. contributed reagents, materials and/or analysis tools. A.R., H.Q., Y.Y., K.B. and N.H. wrote the manuscript.

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Correspondence to Neil Hunter.

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Reynolds, A., Qiao, H., Yang, Y. et al. RNF212 is a dosage-sensitive regulator of crossing-over during mammalian meiosis. Nat Genet 45, 269–278 (2013). https://doi.org/10.1038/ng.2541

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