TI - Connecting Crossover Control and Chromosome Structures . AB - Spo11+/-Atm-/- spermatocytes exhibited numerous defects in chromosome axes . It is possible that the structural flaws reflect defects in axis morphogenesis , but as discussed below there is also reason to consider that the lack of ATM causes defects in axis stability . Previous studies noted chromosome fragmentation in Atm-/- spermatocytes but were unable to distinguish whether this defect was an indirect effect of arrest and apoptosis in early to mid prophase [22] . Since progression through meiotic prophase I is substantially rescued in Spo11+/-Atm-/- spermatocytes , our results indicate that axis defects are more directly tied to the lack of ATM . The crossover and chromosome axis defects in Spo11+/-Atm-/- spermatocytes may be separate . However , considerations about the relationship between meiotic recombination and higher order chromosome structures lead us to speculate instead that these defects may be manifestations of a single underlying problem . In many organisms , mutations affecting chromosome structure proteins perturb meiotic recombination and , conversely , mutations affecting recombination factors perturb chromosome structures [reviewed in 36,49] . Moreover , cytological and molecular studies reveal that meiotic recombination occurs in close spatial coordination with chromosome axes ( reviewed in [49] ) . Taken together , these observations reveal functional connections between recombination and axes . It has been argued that these connections are important for establishing a functional chiasma , because a chiasma is more than just a crossover at the DNA level--a chiasma also involves higher order chromosome structure changes , including exchange of the chromosome axes and local separation of sister chromatids [5] , [49] , [59] . In order for chromosome structures and recombination events to develop in parallel , signals coordinating these processes must be transduced in both directions between the axes and the recombination machinery . Moreover , chromosome axes are likely to participate directly in crossover control by providing a conduit for an interference signal that governs distribution of crossovers [5] , [60] . We propose that ATM kinase activity generates or transduces one or more of these signals . Consistent with this interpretation , mutations of Mre11 and Nbs1 that attenuate ATM signaling also cause crossover control defects in mouse spermatocytes [46] . Relevant PHOSphorylation targets remain to be identified , but might include histones , structural components of the axes , and recombination proteins ( see also [27] , [58] ) . Non-catalytic ( ie , kinase -independent ) functions of ATM are also possible [61] . This model suggests how axis and recombination perturbations could both arise from absence of ATM . Sites of ongoing recombination are also places where axes are locally destabilized , for example showing buckling or twisting of the axes ( reviewed in [49] , [62] ) . If Atm-/- mutants are defective for interactions between recombinosomes and the axes ( eg , if ATR is only partly effective as a substitute ) , then correlated defects would be expected in all of the processes that depend on these interactions . If correct , this model predicts that axial interruptions in Spo11+/-Atm-/- spermatocytes occur specifically at sites where DSBs have occurred . The observed correlation between chromosomal anomalies and persistent gammaH2AX , RAD51 and RPA foci at pachynema in these mice is consistent with this prediction . Moreover , we found that axis defects that result in overt chromosome fragmentation in the absence of ATM are spatially correlated with chromosomal regions where crossover control is known to play an important role--the short SC fragments in Spo11+/-Atm-/- spermatocytes were usually derived from the distal tips of chromosomes , and there is a known preference in spermatocytes for one ( or the only ) crossover on a bivalent to be located distally [12] , [51] . This nonrandom positioning is thought to be another manifestation of crossover control [51] , [63] . Thus , the position of fragmentation is consistent with our hypothesis that axis and crossover control defects are functionally connected . The meiotic cell's ability to coordinate multiple molecular processes spanning size scales that differ by orders of magnitude is truly remarkable . The unexpected rescue by Spo11 hemizygosity of meiotic prophase progression in Atm-/- spermatocytes has allowed us to identify ATM as a prime candidate to be directly involved in this unique feature of meiotic chromosome dynamics .