Meiotic crossover formation between homologous chromosomes (homologues) entails DNA double-strand break (DSB) formation, homology search using DSB ends, and synaptonemal-complex formation coupled with DSB repair. Meiotic progression must be prevented until DSB repair and homologue alignment are completed, to avoid the formation of aneuploid gametes. Here we show that mouse HORMAD1 ensures that sufficient numbers of processed DSBs are available for successful homology search. HORMAD1 is needed for normal synaptonemal-complex formation and for the efficient recruitment of ATR checkpoint kinase activity to unsynapsed chromatin. The latter phenomenon was proposed to be important in meiotic prophase checkpoints in both sexes. Consistent with this hypothesis, HORMAD1 is essential for the elimination of synaptonemal-complex-defective oocytes. Synaptonemal-complex formation results in HORMAD1 depletion from chromosome axes. Thus, we propose that the synaptonemal complex and HORMAD1 are key components of a negative feedback loop that coordinates meiotic progression with homologue alignment: HORMAD1 promotes homologue alignment and synaptonemal-complex formation, and synaptonemal complexes downregulate HORMAD1 function, thereby permitting progression past meiotic prophase checkpoints.
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We thank A. Hientzsch and K. Duerschke for general laboratory support and technical assistance; R. Jessberger for sharing ideas, antibodies (anti-SYCP3, anti-STAG3 and anti-SMC3) and support; F. Baudat and B. De Massy for providing us with Spo11+/− mice; J. Chen for the anti-TOPBP1 antibody; E. Marcon for the anti-RPA antibody; C. Höög for anti-SYCE1 and anti-SYCE2 antibodies; G.C. Enders for the anti-GCNA antibody; and M.P. Thelen for the anti-SPO11 antibody. We are grateful to M. Siomos and D. Knapp for discussion, revising and proofreading the manuscript. The Deutsche Forschungsgemeinschaft (DFG; grants: TO421/4-1 SPP1384 and TO421/3-1) and the Sächsisches Staatsministerium für Wissenschaft und Kunst supported K.D. and A.T.; Grants HD53855 and HD40916 from the US National Institutes of Health supported J.L., I.R., M.J. and S.K.; ARC (Subvention fixe 1143) and La Ligue Regionale (RS09/75-39) supported K.H. and K.W.; the Medical Research Council UK supported H.J.C.; the DFG research centre and cluster of excellence to the Center for Regenerative Therapies Dresden (CRTD) supported the work of K.A.; a CRTD seed grant supported K.A. and A.T.; and an EFRE grant (Europäischer Fonds für Regionale Entwicklung) supported K.A., J.F. and A.F.S.
The authors declare no competing financial interests.
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Daniel, K., Lange, J., Hached, K. et al. Meiotic homologue alignment and its quality surveillance are controlled by mouse HORMAD1. Nat Cell Biol 13, 599–610 (2011). https://doi.org/10.1038/ncb2213
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