Crossover recombination facilitates the accurate segregation of homologous chromosomes during meiosis1,2. In mammals, poorly characterized regulatory processes ensure that every pair of chromosomes obtains at least one crossover, even though most recombination sites yield non-crossovers3. Designation of crossovers involves selective localization of the SUMO ligase RNF212 to a minority of recombination sites, where it stabilizes pertinent factors such as MutSγ (ref. 4). Here we show that the ubiquitin ligase HEI10 (also called CCNB1IP1)5,6 is essential for this crossover/non-crossover differentiation process. In HEI10-deficient mice, RNF212 localizes to most recombination sites, and dissociation of both RNF212 and MutSγ from chromosomes is blocked. Consequently, recombination is impeded, and crossing over fails. In wild-type mice, HEI10 accumulates at designated crossover sites, suggesting that it also has a late role in implementing crossing over. As with RNF212, dosage sensitivity for HEI10 indicates that it is a limiting factor for crossing over. We suggest that SUMO and ubiquitin have antagonistic roles during meiotic recombination that are balanced to effect differential stabilization of recombination factors at crossover and non-crossover sites.
Variants in the RNF212 and CCNB1IP1 (HEI10) genes are associated with heritable variation in the rate of crossing over in humans7,8,9,10. The encoded RNF212 and HEI10 proteins also have structural and functional similarities. Both proteins have tripartite structures, with RING, coiled-coil and tail domains, and are inferred to catalyze post-translational protein modification by ubiquitin-like proteins4,5,6,11,12. RNF212 is implicated as an E3 enzyme for SUMO modification, whereas HEI10 has ubiquitin ligase activity (refs. 4,5,11 and Y.Y. and N.H., unpublished observation). In both Hei10mei4/mei4 and Rnf212−/− mutant mice, early stages of meiosis occur normally, and full synapsis of homologous chromosomes (homologs) is achieved4,6 (mei4 is an allele of Ccnb1ip1, also known as Hei10). However, crossover-specific recombination complexes, containing the MutLγ complex (MLH1 and MLH3) and cyclin-dependent kinase CDK2, do not assemble4,6. Consequently, crossing over fails, and the mice are sterile. These similarities prompted us to examine the relationship between these two pro-crossover factors.
Using immunofluorescence cytology, we previously described the dynamic localization of RNF212 to synaptonemal complexes4, the meiosis-specific structures that connect homologs along their lengths during the pachytene stage of meiosis. As homologs undergo synapsis during zygonema, RNF212 localizes specifically to the central region of synaptonemal complexes, forming a punctate pattern of immunostaining foci. Consistent with previous analysis4, in wild-type spermatocytes at early pachynema, when synapsis is complete, we observed ∼150 foci per nucleus (Fig. 1a,k). By midpachynema, most staining had disappeared, and RNF212 foci were retained only at sites where crossovers form (Fig. 1b,c,k). These crossover-specific RNF212 foci were then lost by late pachynema, before the disassembly of synaptonemal complexes at diplonema (Fig. 1d,e,k).
In spermatocytes from Hei10mei4/mei4 mice, the early staining pattern of abundant RNF212 foci appeared normal (155.9 ± 37.2 (s.d.) foci, 20 early pachytene nuclei versus 153.0 ± 42.8 foci in wild-type spermatocytes, 20 nuclei; Fig. 1f,k). Strikingly, this pattern persisted throughout pachynema, and loss of RNF212 from the chromosomes was only seen when synaptonemal complexes were disassembled during diplonema (Fig. 1g–k). Moreover, the numbers of RNF212 foci were significantly higher than ever seen in wild-type spermatocytes (P = 0.0003, Mann-Whitney test). Thus, HEI10 is required for the turnover of RNF212 after synapsis that culminates in its selective retention at future crossover sites.
To examine the consequences of persistent RNF212 for recombination in Hei10mei4/mei4 mutants, we examined the chromosomal dynamics of the MutSγ complex (Fig. 2). MutSγ comprises MSH4 and MSH5, two meiosis-specific homologs of the bacterial DNA mismatch-binding factor MutS13. Published studies indicate that MutSγ binds and stabilizes DNA strand-exchange intermediates to promote both homolog synapsis and crossing over14,15. We previously showed4 that a minority of MutSγ foci present in early pachynema colocalize with RNF212. Analysis of Rnf212−/− mice indicated that RNF212 acts to stabilize MutSγ and thereby designate a crossover fate to this subset of recombination sites.
Here we confirmed that the chromosomal localization of MutSγ in wild-type spermatocytes resembled that of RNF212: specifically, 82.9 ± 23.4 (s.d.) MSH4 immunostaining foci were observed in late zygonema and early pachynema, whereas at midpachynema only 39.4 ± 9.6 foci were retained, and MSH4 staining had essentially disappeared by the onset of diplonema (Fig. 2a–e,k). In Hei10mei4/mei4 mutant spermatocytes, the chromosomal dynamics of MutSγ were severely aberrant. Although normal numbers of MSH4 foci were formed at late zygonema/early pachynema, focus numbers remained high throughout pachynema and only decreased after homologs desynapsed at diplonema (Fig. 2f–k).
Super-resolution structured illumination microscopy (SIM)16 showed that the stabilization of MutSγ foci correlated with the degree of colocalization of MutSγ and RNF212 (Fig. 2l–p and Supplementary Fig. 1). Consistent with our previous analysis4, around a third of MSH4 foci colocalized with RNF212 in late-zygotene and early pachytene spermatocytes (Fig. 2l,m,p and Supplementary Fig. 1). In sharp contrast, in Hei10mei4/mei4 mutant spermatocytes, MSH4 foci showed a high level of colocalization (∼90%) with RNF212 foci at all stages from early zygonema through early diplonema (Fig. 2n–p and Supplementary Fig. 1). These observations lend further support to our inference that RNF212 stabilizes the association of MutSγ with recombination sites4. Thus, RNF212 and HEI10 have antagonistic functions with respect to the stabilization of MutSγ at recombination sites. We suggest that the balance of their two activities underpins the temporal dynamics and spatial patterning of RNF212 and MutSγ seen in wild-type spermatocytes.
Meiotic recombination is initiated by the programed formation of DNA double-strand breaks (DSBs)15. The persistence of MutSγ complexes implies that DSB repair is delayed in Hei10mei4/mei4 spermatocytes. Immunostaining for DSB-induced H2AX phosphorylation (γH2AX) supported this inference (Fig. 3). In wild-type nuclei, γH2AX staining initially formed a pan-nuclear cloud, which diminished to limited chromatin flares and foci as chromosome synapsis ensued and finally disappeared from autosomes around midpachynema17 (Fig. 3a–e,k; note that γH2AX accumulated as a large staining body on the chromatin of the sex chromosomes, where it facilitates transcriptional silencing18). In Hei10mei4/mei4 spermatocytes, although pan-nuclear γH2AX staining diminished with synapsis, delayed DSB repair was indicated by the persistence of γH2AX foci throughout pachynema (Fig. 3f–j,k). Ultimately, however, DSBs appear to be repaired in Hei10mei4/mei4 spermatocytes, as broken chromatids are not detected in late-stage nuclei6. Together, these data suggest that HEI10-dependent elimination of RNF212 from synaptonemal complexes is required for the timely removal of MutSγ from most recombination sites as pachynema progresses. This in turn allows the timely progression of recombination and the repair of DSBs.
Despite their broadly similar phenotypes, we can now conclude that Rnf212−/− and Hei10mei4/mei4 mutants have distinct defects with respect to the designation of crossover sites. In the absence of RNF212, the designation of crossover sites fails because no MutSγ complexes are stabilized beyond early pachynema4, whereas the absence of HEI10 causes most or all MutSγ complexes to be stabilized, as though all sites had been designated a crossover fate. These findings raise the following question: why do Hei10mei4/mei4 mutants not form numerous crossovers?
Insights into this question, as well as into how HEI10 regulates the dynamics of RNF212 and MutSγ , came from examining the chromosomal localization pattern of HEI10. Although previous attempts to localize mouse HEI10 to meiotic chromosomes have been unsuccessful6, we were able to show that mouse HEI10 associates with synaptonemal complexes to form distinct immunostaining foci (Fig. 4a–k and Supplementary Figs. 2 and 3). Unlike RNF212, distinct foci of HEI10 were rarely detected along nascent synaptonemal complexes during zygonema (Fig. 4a). Given that Hei10mei4/mei4 phenotypes are already apparent at this time (for example, Fig. 2p), we infer that cytologically undetectable HEI10 regulates the early stage dynamics of RNF212 and MutSγ. Indeed, the possibility that this function of HEI10 does not involve association with meiotic chromosomes cannot be ruled out. However, by early pachynema, HEI10 foci could be detected (Fig. 4c,d), and their numbers peaked during midpachynema with an average of 27 foci per nucleus (27.2 ± 8.8 (s.d.) foci, 22 nuclei; Fig. 4e,f,k). At this stage, HEI10 focus numbers were quite variable, with as few as 15 and as many as 50 foci per nucleus. In late-pachytene nuclei, the average HEI10 focus number was lower and was less variable (21.1 ± 3.6 (s.d.) foci, 20 nuclei; Fig. 4g,h,k). At the onset of diplonema, HEI10 foci were no longer detected (Fig. 4i,j).
As HEI10 promotes loss of RNF212 and MutSγ from synaptonemal complexes, we examined the colocalization of these proteins (Fig. 4l–o). In midpachytene spermatocytes, only 23% of RNF212 foci and 29% of MSH4 foci colocalized with HEI10 (respectively, 22.6 ± 7.7% (s.d.) and 28.9 ± 15.1% foci, 10 nuclei each). HEI10 is required for the formation of crossover-specific complexes containing CDK2 and MutLγ (MLH1-MLH3). In contrast to what was observed for RNF212 and MSH4, a high degree of colocalization was seen for these markers and HEI10 (Fig. 4p–s): 74.0 ± 10.7% (s.d.) of non-telomeric CDK2 foci and 94.3 ± 6.9% of MLH1 foci colocalized with HEI10 (10 and 19 nuclei, respectively). These data are consistent with HEI10 foci superseding complexes of RNF212 and MutSγ at future crossover sites.
We investigated the genetic requirements for the chromosomal localization of HEI10 using several mutant lines (Fig. 5). SPO11 catalyzes DNA breakage to initiate recombination15. In Spo11−/− spermatocytes, homolog pairing is defective, but a substantial fraction of nuclei assemble incomplete synaptonemal complexes, which generally involve non-homologous chromosomes19,20. We found that the numbers of HEI10 foci were diminished, although foci were not completely eliminated, in these nuclei (Fig. 5a,b,g). This dependency contrasts that of RNF212, which readily associates with synaptonemal complexes independent of recombination4.SYCP1 is a major component of the synaptonemal complex central region21. In Sycp1−/− mice, meiotic recombination initiates normally and homologs closely coalign, but synapsis is precluded. In addition, MutLγ foci are not detected in Sycp1−/− nuclei, indicating that the designation or maturation of crossover sites fails in this mutant. We found that the formation of HEI10 foci was greatly reduced in pachytene-like Sycp1−/− spermatocytes, but most nuclei contained a few foci (4.5 ± 3.1 (s.d.) foci per nucleus, 20 nuclei; Fig. 5c,d,g). In Rnf212−/− mutants, homologs undergo synapsis but the designation of crossover sites is defective4. As in the Sycp1−/− mutants, we observed that a few HEI10 foci were detected in Rnf212−/− mutant spermatocytes (6.7 ± 4.9 (s.d.) foci, 23 nuclei; Fig. 5e–g). We infer that the initiation of recombination, homolog synapsis and the designation of crossover sites are important for the normal formation and/or stabilization of HEI10 foci.
Finally, we examined HEI10 localization in mice lacking the MLH3 component of the crossover-specific factor MutLγ (ref. 13). In Mlh3−/− spermatocytes, homolog synapsis and the initial designation of crossover sites appear normal, but the implementation of crossing over fails4,22. In sharp contrast to the other mutants we examined, high numbers of HEI10 foci were observed in Mlh3−/− spermatocytes (Fig. 5h–m). Unlike in wild-type mice, HEI10 foci were already detectable in zygonema (Fig. 5h,i,n), reached very high numbers during midpachynema (89.9 ± 24.5 (s.d.) foci per nucleus, 21 nuclei; Fig. 5j,k,n) and persisted into diplonema (Fig. 5l–n). At least half of the foci in midpachynema were coincident with γH2AX staining (53.0 ± 12.5% (s.d.) foci, 10 nuclei; Supplementary Fig. 4), implying that the majority of HEI10 accumulates at sites of DSB repair in Mlh3−/− cells.
These data suggest that the chromosomal localization of HEI10 occurs in two phases. First, HEI10 is licensed to accumulate into foci associated with synaptonemal complexes. These complexes, normally transient, may generally promote the progression of recombination. In wild-type cells, the relatively high and variable numbers of HEI10 foci seen in midpachynema may be a manifestation of this first phase. Subsequently, stable accumulation of HEI10 specifically at crossover sites is directed by MLH3 (and presumably by MLH1). Notably, MLH3 restrains accumulation of HEI10 during zygonema, an early function that was not anticipated from the timing of crossover-specific MLH3 foci, which do not appear until early to mid-pachynema13.
Taken together, our data imply that HEI10 functions during zygonema to limit the colocalization of RNF212 with MutSγ-associated recombination sites and thereby establish early differentiation of crossover and non-crossover sites. Later, HEI10 is directed by MutLγ (and perhaps by CDK2) to stably accumulate at designated crossover sites. Here we propose that HEI10 also promotes the dissociation of RNF212 and MutSγ to allow the progression of recombination and the implementation of the final steps of crossing over. The model in Supplementary Figure 5 synthesizes the key points of our analysis and those of previous studies.
Recently, recombination rate in humans has been associated with a variant in the 5′ UTR of CNNB1IP1 (HEI10)10 that has the potential to alter expression levels, suggesting that HEI10 may be a dosage-sensitive regulator of crossing over. To determine whether the crossover function of mouse HEI10 is dosage sensitive, we analyzed spermatocytes from Hei10+/mei4 heterozygotes (Fig. 6). Indeed, significant decreases in the numbers of HEI10 foci (20.6%), MLH1 foci (13.5%) and chiasmata (10%) were detected (P = 0.0003, P < 0.0001 and P = 0.0088, respectively, Mann-Whitney test). In spermatocytes, homologs not tethered by crossovers are detected by the spindle checkpoint, which triggers apoptosis23. Consistent with the reduced crossing over seen in Hei10+/mei4 heterozygotes, we detected a significant increase in the number of apoptotic (TUNEL-positive) cells in testes sections from Hei10+/mei4 heterozygotes (P < 0.0001, Mann-Whitney test; Fig. 6j–m and Supplementary Fig. 6).
Intriguingly, the crossover function of RNF212 also shows dosage sensitivity in the mouse, and human RNF212 variants have been associated with changes in recombination rate4,7,8,9. These observations are consistent with the idea that a balance between SUMO and ubiquitin is a key aspect of crossover regulation. It will be interesting to see whether human alleles of CNNB1IP1 (HEI10), RNF212 and genes encoding recombination factors such as MutSγ interact to modulate recombination rate, fertility and the risk of aneuploidy.
All mice were congenic with the C57BL/6J background. Mice were maintained and used for experimentation according to the guidelines of the Institutional Animal Care and Use Committees of the University of California, Davis, and the Middlebury College Animal Facility. The Hei10, Mlh3, Rnf212, Spo11 and Sycp1 mutant lines and primer sequences for genotyping were previously described4,6,19,21,22. Male mice between 2–6 months of age were used for experimentation.
Protein blot analysis.
Tissues from adult mice were sonicated in RIPA buffer, protein concentration was measured by the Bradford assay, and 100–200 μg of protein was separated by SDS-PAGE. After protein transfer to nitrocellulose membranes (Waterman), blots were incubated overnight with the following antibodies: mouse monoclonal antibody to CCNB1IP1/HEI10 (ab118999, Abcam; 1:2,000 dilution), rabbit polyclonal antibody to CCNB1IP1/HEI10 (this study; 1:2,000 dilution) or mouse antibody to tubulin (BioLegend, 625902; 1:2,000 dilution). Secondary antibodies (1:10,000 dilution) were goat antibody to rabbit or mouse IgG conjugated to horseradish peroxidase (HRP; SouthernBiotech, 4050-05 and 1031-05, respectively). HRP was detected using ECL reagent (Pierce).
A polyclonal antibody against mouse HEI10/CCNB1IP1 was raised in rabbits against a mixture of two C-terminal peptides. Antibodies were purified from serum using Protein A/G spin columns (GE Healthcare). Antibody specificity was determined by protein blotting and immunofluorescence staining of material from wild-type and Hei10mei4/mei4 mice.
Testes and ovaries were dissected from freshly killed mice and processed for surface spreading as described24. Sample size was determined empirically; for all quantification, images from at least two mice (n = 2–5) were analyzed. Comparisons were made between mice that were either littermates or were matched by age. All cytological analyses were performed by two observers; the second observer was blinded to which group or genotype was being analyzed. Immunofluorescence staining was performed as described25 using the following primary antibodies with incubation overnight at room temperature: mouse antibody to SYCP3 (sc-74568, Santa Cruz Biotechnology; 1:200 dilution), rabbit antibody to SYCP3 (sc-33195, Santa Cruz Biotechnology; 1:300 dilution), guinea pig antibody to SYCE1 (1:2,000 dilution) (generously provided by C. Höög, Karolinska Institutet)26, guinea pig antibody to RNF212 (1:50 dilution)4, rabbit antibody to RNF212 (1:200 dilution)4, rabbit antibody to MSH4 (ab58666, Abcam; 1:100 dilution), mouse monoclonal antibody to CCNB1IP1/HEI10 (ab118999, Abcam; 1:150 dilution), rabbit polyclonal antibody to CCNB1IP1/HEI10 (this study), mouse antibody to MLH1 (550838, BD Pharmingen; 1:50 dilution), mouse monoclonal antibody to γH2AX (05-636, Millipore; 1:500 dilution), mouse monoclonal antibody to CDK2 (sc-6248, Santa Cruz Biotechnology; 1:200 dilution) and guinea pig antibody to H1t (a gift from M.A. Handel, Jackson Laboratory; 1:1,000 dilution)27. Slides were subsequently incubated with the following goat secondary antibodies for 1 h at 37 °C: anti-rabbit 488 (A11070, Molecular Probes; 1:1,000 dilution), anti-rabbit 568 (A11036, Molecular Probes; 1:2,000 dilution), anti-mouse 555 (A21425, Molecular Probes; 1:1,000 dilution), anti-mouse 594 (A11020, Molecular Probes; 1:1,000 dilution), anti-mouse 488 (A11029, Molecular Probes; 1:1,000 dilution) and anti–guinea pig fluorescein isothiocyanate (106-096-006 FITC, Jackson Labs; 1:200 dilution). Coverslips were mounted with ProLong Gold antifade reagent (Molecular Probes). For chiasma counts, air-dried preparations of cells in diakinesis/metaphase I were prepared as described28 and stained with DAPI.
Testes were fixed in formalin, embedded in paraffin, sectioned and processed using the ApopTag Plus Peroxidase In Situ Apoptosis Detection kit (Chemicon).
Immunolabeled chromosome spreads and DAPI-stained diakinesis/metaphase I nuclei were imaged using a Zeiss AxioPlan II microscope with a 63× Plan Apochromat 1.4 objective and an EXFO X-Cite metal halide light source. Images were captured by a Hamamatsu ORCA-ER CCD camera and processed using the Volocity (Perkin Elmer) and Photoshop (Adobe) software packages. SIM analysis was performed using a Nikon N-SIM super-resolution microscope system and NIS-Elements 2 image-processing software. MSH4-RNF212 colocalization was determined using NIS-Elements, and cofoci were confirmed by visual inspection. Testes sections were imaged using an Axiovert 200 microscope and AxioCamMRc camera with AxioVision 4.4 software. Apoptotic cells were imaged and counted in representative fields of view.
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We thank A. Kong for communicating unpublished results. This work was supported by US National Institutes of Health (NIH) grants R01GM084955 to N.H., R01GM45415 to J.S. and HD041012 to P.E.C. and by National Science Foundation grant CAREER 0844941 to J.W. N.H. is an investigator of the Howard Hughes Medical Institute.
The authors declare no competing financial interests.
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Qiao, H., Prasada Rao, H., Yang, Y. et al. Antagonistic roles of ubiquitin ligase HEI10 and SUMO ligase RNF212 regulate meiotic recombination. Nat Genet 46, 194–199 (2014). https://doi.org/10.1038/ng.2858
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