title: Homeostatic control of recombination is implemented progressively in mouse meiosis.
abstract: Humans suffer from high rates of fetal aneuploidy, often arising from the absence of meiotic crossover recombination between homologous chromosomes. Meiotic recombination is initiated by double-strand breaks (DSBs) generated by the SPO11 transesterase. In yeast and worms, at least one buffering mechanism, crossover homeostasis, maintains crossover numbers despite variation in DSB numbers. 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.
authors.affiliation: Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cole
authors.forename: Liisa
authors.initials: L
authors.lastname: Kauppi
authors.forename: Julian
authors.initials: J
authors.lastname: Lange
authors.forename: Ignasi
authors.initials: I
authors.lastname: Roig
authors.forename: Raymond
authors.initials: R
authors.lastname: Wang
authors.forename: Scott
authors.initials: S
authors.lastname: Keeney
authors.forename: Maria
authors.initials: M
authors.lastname: Jasin
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D008297:Male; D008540:Meiosis / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D028044:Phosphate-Binding Proteins; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics*; D013090:Spermatocytes / Q000378:metabolism; D000099257:Meiotic Recombination Protein SPO11
chemical_list: D018797:Cell Cycle Proteins; D004706:Endodeoxyribonucleases; D009687:Nuclear Proteins; D028044:Phosphate-Binding Proteins; D051135:Rad51 Recombinase; D000099257:Meiotic Recombination Protein SPO11; C513032:Dmc1 protein, mouse; C495154:Rad51 protein, mouse