title: Numerical constraints and feedback control of double-strand breaks in mouse meiosis.
abstract: Different organisms display widely different numbers of the programmed double-strand breaks (DSBs) that initiate meiotic recombination (e.g., hundreds per meiocyte in mice and humans vs. dozens in nematodes), but little is known about what drives these species-specific DSB set points or the regulatory pathways that control them. Here we examine male mice with a lowered dosage of SPO11, the meiotic DSB catalyst, to gain insight into the effect of reduced DSB numbers on mammalian chromosome dynamics. An approximately twofold DSB reduction was associated with the reduced ability of homologs to synapse along their lengths, provoking prophase arrest and, ultimately, sterility. In many spermatocytes, chromosome subsets displayed a mix of synaptic failure and synapsis with both homologous and nonhomologous partners ("chromosome tangles"). The X chromosome was nearly always involved in tangles, and small autosomes were involved more often than large ones. We conclude that homolog pairing requirements dictate DSB set points during meiosis. Importantly, our results reveal that karyotype is a key factor: Smaller autosomes and heteromorphic sex chromosomes become weak links when DSBs are reduced below a critical threshold. Unexpectedly, unsynapsed chromosome segments trapped in tangles displayed an elevated density of DSB markers later in meiotic prophase. The unsynapsed portion of the X chromosome in wild-type males also showed evidence that DSB numbers increased as prophase progressed. These findings point to the existence of a feedback mechanism that links DSB number and distribution with interhomolog interactions.
authors.affiliation: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Liisa
authors.initials: L
authors.lastname: Kauppi
authors.forename: Marco
authors.initials: M
authors.lastname: Barchi
authors.forename: Julian
authors.initials: J
authors.lastname: Lange
authors.forename: Frédéric
authors.initials: F
authors.lastname: Baudat
authors.forename: Maria
authors.initials: M
authors.lastname: Jasin
authors.forename: Scott
authors.initials: S
authors.lastname: Keeney
mesh_terms: D000818:Animals; D002875:Chromosomes / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D008297:Male; D008540:Meiosis / Q000235:genetics*; D051379:Mice; D013573:Synaptonemal Complex / Q000235:genetics / Q000378:metabolism; D000099257:Meiotic Recombination Protein SPO11
chemical_list: D004706:Endodeoxyribonucleases; D000099257:Meiotic Recombination Protein SPO11