The ATM Signaling Cascade Promotes Recombination-Dependent Pachytene Arrest in Mouse Spermatocytes
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{"title"=>"The ATM Signaling Cascade Promotes Recombination-Dependent Pachytene Arrest in Mouse Spermatocytes", "type"=>"journal", "authors"=>[{"first_name"=>"Sarai", "last_name"=>"Pacheco", "scopus_author_id"=>"56579941500"}, {"first_name"=>"Marina", "last_name"=>"Marcet-Ortega", "scopus_author_id"=>"56560112900"}, {"first_name"=>"Julian", "last_name"=>"Lange", "scopus_author_id"=>"12797931700"}, {"first_name"=>"Maria", "last_name"=>"Jasin", "scopus_author_id"=>"7005221713"}, {"first_name"=>"Scott", "last_name"=>"Keeney", "scopus_author_id"=>"7005614687"}, {"first_name"=>"Ignasi", "last_name"=>"Roig", "scopus_author_id"=>"24345435300"}], "year"=>2015, "source"=>"PLoS Genetics", "identifiers"=>{"issn"=>"15537404", "scopus"=>"2-s2.0-84926140145", "sgr"=>"84926140145", "pui"=>"603514000", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)", "pmid"=>"25768017", "doi"=>"10.1371/journal.pgen.1005017"}, "id"=>"feff9ddb-af9a-38b1-b341-321c7d03b451", "abstract"=>"Most mutations that compromise meiotic recombination or synapsis in mouse spermatocytes result in arrest and apoptosis at the pachytene stage of the first meiotic prophase. Two main mechanisms are thought to trigger arrest: one independent of the double-strand breaks (DSBs) that initiate meiotic recombination, and another activated by persistent recombination intermediates. Mechanisms underlying the recombination-dependent arrest response are not well understood, so we sought to identify factors involved by examining mutants deficient for TRIP13, a conserved AAA+ ATPase required for the completion of meiotic DSB repair. We find that spermatocytes with a hypomorphic Trip13 mutation (Trip13mod/mod) arrest with features characteristic of early pachynema in wild type, namely, fully synapsed chromosomes without incorporation of the histone variant H1t into chromatin. These cells then undergo apoptosis, possibly in response to the arrest or in response to a defect in sex body formation. However, TRIP13-deficient cells that additionally lack the DSB-responsive kinase ATM progress further, reaching an H1t-positive stage (i.e., similar to mid/late pachynema in wild type) despite the presence of unrepaired DSBs. TRIP13-deficient spermatocytes also progress to an H1t-positive stage if ATM activity is attenuated by hypomorphic mutations in Mre11 or Nbs1 or by elimination of the ATM-effector kinase CHK2. These mutant backgrounds nonetheless experience an apoptotic block to further spermatogenic progression, most likely caused by failure to form a sex body. DSB numbers are elevated in Mre11 and Nbs1 hypomorphs but not Chk2 mutants, thus delineating genetic requirements for the ATM-dependent negative feedback loop that regulates DSB numbers. The findings demonstrate for the first time that ATM-dependent signaling enforces the normal pachytene response to persistent recombination intermediates. Our work supports the conclusion that recombination defects trigger spermatocyte arrest via pathways than are genetically distinct from sex body failure-promoted apoptosis and confirm that the latter can function even when recombination-dependent arrest is inoperative. Implications of these findings for understanding the complex relationships between spermatocyte arrest and apoptosis are discussed.", "link"=>"http://www.mendeley.com/research/atm-signaling-cascade-promotes-recombinationdependent-pachytene-arrest-mouse-spermatocytes", "reader_count"=>37, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Student > Doctoral Student"=>5, "Researcher"=>11, "Student > Ph. D. Student"=>9, "Student > Postgraduate"=>1, "Student > Master"=>8, "Student > Bachelor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Student > Doctoral Student"=>5, "Researcher"=>11, "Student > Ph. D. Student"=>9, "Student > Postgraduate"=>1, "Student > Master"=>8, "Student > Bachelor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>10, "Agricultural and Biological Sciences"=>23, "Medicine and Dentistry"=>2, "Veterinary Science and Veterinary Medicine"=>1, "Sports and Recreations"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Sports and Recreations"=>{"Sports and Recreations"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>23}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>10}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>1}}, "reader_count_by_country"=>{"Netherlands"=>1, "United States"=>2}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1947033"], "description"=>"<p>SPO11-oligonucleotide complexes were immunoprecipitated from extracts of testes of the indicated genotypes, labelled with terminal transferase and <sup>32</sup>P-nucleotide, and resolved by SDS-PAGE. Top image in each panel, autoradiograph; bottom image, SPO11 Western blot where the two major SPO11 isoforms, α and β, are indicated. The vertical lines next to the autoradiographs indicate the signal from SPO11-oligonucleotide complexes. Asterisk indicates non-specific signal from the labelling reaction. Short arrow designates the migration position of the heavy chain of the antibody used to immunoprecipitate SPO11. (A-B) Both <i>Mre11</i> and <i>Nbs1</i> mutants have increased levels of SPO11-oligonucleotide complexes compared to littermate controls (1.9 ± 0.4 fold, mean ± SD of the relative signal intensity compared to a wild-type control, n = 3 mice, and 1.8 ± 0.2 fold, n = 3, respectively). (C) SPO11-oligonucleotide complex levels are slightly reduced in <i>Trip13</i><sup><i>mod/mod</i></sup> samples (0.7 ± 0.2, n = 3), similar to other recombination-deficient mutants, such as <i>Dmc1</i><sup>–/–</sup> [<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005017#pgen.1005017.ref027\" target=\"_blank\">27</a>]. The SPO11α isoform is not detected in <i>Trip13</i><sup><i>mod/mod</i></sup> testes as observed in other mutants that arrest at pachynema [<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005017#pgen.1005017.ref027\" target=\"_blank\">27</a>]. (D) <i>Chk2</i><sup>−/−</sup> testes have similar levels of SPO11-oligonucleotide complex as controls (1.0 ± 0.2 fold, n = 3).</p>", "links"=>[], "tags"=>["histone variant H 1t", "Trip 13mod arrest", "CHK", "hypomorphic Trip 13 mutation", "compromise meiotic recombination", "spermatocyte arrest", "meiotic DSB repair", "Chk 2 mutants", "MRE 11", "apoptosi", "H 1t stage", "DSB numbers", "aaa", "Nbs 1 hypomorphs", "recombination intermediates", "sex body formation", "response", "mouse spermatocytes result"], "article_id"=>1334363, "categories"=>["Biological Sciences"], "users"=>["Sarai Pacheco", "Marina Marcet-Ortega", "Julian Lange", "Maria Jasin", "Scott Keeney", "Ignasi Roig"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005017.g004", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_MRE11_complex_but_not_TRIP13_or_CHK2_modulates_SPO11_oligonucleotide_complex_levels_/1334363", "title"=>"The MRE11 complex, but not TRIP13 or CHK2, modulates SPO11-oligonucleotide complex levels.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-13 02:43:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/1947051"], "description"=>"<p>N.T.W.: Normalized Testis Weight expressed as a percentage of body weight.</p><p><sup>a</sup>: one mouse analysed.</p><p>*: Significantly different from what is found in <i>Trip13</i><sup><i>mod/mod</i></sup> mice, P˂0.05, Fisher’s exact test.</p><p>Testicular and meiotic phenotypes of wild-type and mutant mice.</p>", "links"=>[], "tags"=>["histone variant H 1t", "Trip 13mod arrest", "CHK", "hypomorphic Trip 13 mutation", "compromise meiotic recombination", "spermatocyte arrest", "meiotic DSB repair", "Chk 2 mutants", "MRE 11", "apoptosi", "H 1t stage", "DSB numbers", "aaa", "Nbs 1 hypomorphs", "recombination intermediates", "sex body formation", "response", "mouse spermatocytes result"], "article_id"=>1334377, "categories"=>["Biological Sciences"], "users"=>["Sarai Pacheco", "Marina Marcet-Ortega", "Julian Lange", "Maria Jasin", "Scott Keeney", "Ignasi Roig"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005017.t001", "stats"=>{"downloads"=>0, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Testicular_and_meiotic_phenotypes_of_wild_type_and_mutant_mice_/1334377", "title"=>"Testicular and meiotic phenotypes of wild-type and mutant mice.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-03-13 02:43:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/1947049"], "description"=>"<p>(A-D) Wild-type and <i>Trip13</i><sup><i>mod/mod</i></sup><i>Chk2</i><sup>−/−</sup> pachytene spermatocytes stained for ATR and SYCP3. Arrowheads indicate the sex chromosomes. Note the relatively continuous ATR staining on the X and Y axes in wild type compared with the focal ATR staining in the mutant. (E) Quantification of the different ATR staining patterns found in the genotypes presented. (F) Left panels, percent of early pachytene-stage spermatocytes expressing <i>Zfx</i> and <i>Scml2</i> in wild-type, <i>Trip13</i><sup><i>mod/mod</i></sup>, <i>Trip13</i><sup><i>mod/mod</i></sup><i>Mre11</i><sup><i>ATLD/ATLD</i></sup> and <i>Trip13</i><sup><i>mod/mod</i></sup><i>Chk2</i><sup>−/−</sup> mice. The N value in each bar represents the number of mice analyzed per each gene and genotype. Middle panel, cartoon of a sex body displaying the relative position of <i>Zfx</i> and <i>Scml2</i> within the X chromosome. Right image, representative <i>Trip13</i><sup><i>mod/mod</i></sup><i>Chk2</i><sup>−/−</sup> spermatocyte displaying TOPBP1 (green) and γH2AX (red) immunostaining and <i>Scml2</i> RNA-FISH signal (white, arrow). Just 10.9% ± 3.8 (mean ± SD) of wild-type spermatocytes (N = 225 cells) express <i>Zfx</i> and 17.1% ± 1.9 express <i>Scml2</i> (N = 200). Mouse that fail to synapse the X and Y chromosomes, like <i>Trip13</i><sup><i>mod/mod</i></sup><i>Mre11</i><sup><i>ATLD/ATLD</i></sup>, present more spermatocytes expressing these genes than wild-type mice (for <i>Zfx</i>: 37.1%, N = 35 and for <i>Smcl2</i>: 49.1%, N = 53, P≤0.0001 and P = 0.0002 respectively, Fisher’s exact test). <i>Trip13</i><sup><i>mod/mod</i></sup> mice present more cells expressing these genes than wild-type mice (for <i>Zfx</i>: 27.2% ± 3.2, N = 158; for <i>Smcl2</i>: 27.5% ± 0.0, N = 160, P<0.005, 1 way Anova). Similarly, <i>Trip13</i><sup><i>mod/mod</i></sup><i>Chk2</i><sup>−/−</sup> spermatocytes are more likely to express these X-linked genes than wild-type cells (for <i>Zfx</i>: 28.6%, N = 70; for <i>Smcl2</i>: 30.0%, N = 80, P = 0.0217 and P = 0.0009 respectively, Fisher’s exact test). (G-J) Mid/late pachytene-stage, TUNEL-positive <i>Trip13</i><sup><i>mod/mod</i></sup><i>Chk2</i><sup>−/−</sup> spermatocyte immunostained for SYCP3 (green, H), γH2AX (red, I) and H1t (blue, J). Note the presence of an elongated sex body (arrow), multiple γH2AX patches (arrowhead) and H1t in the chromatin of the apoptotic cell. Bars in (C) and (H) represent 10 μm and apply to panels (A,C) and (G-J), respectively. Bar in (F) represents 5 μm.</p>", "links"=>[], "tags"=>["histone variant H 1t", "Trip 13mod arrest", "CHK", "hypomorphic Trip 13 mutation", "compromise meiotic recombination", "spermatocyte arrest", "meiotic DSB repair", "Chk 2 mutants", "MRE 11", "apoptosi", "H 1t stage", "DSB numbers", "aaa", "Nbs 1 hypomorphs", "recombination intermediates", "sex body formation", "response", "mouse spermatocytes result"], "article_id"=>1334375, "categories"=>["Biological Sciences"], "users"=>["Sarai Pacheco", "Marina Marcet-Ortega", "Julian Lange", "Maria Jasin", "Scott Keeney", "Ignasi Roig"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005017.g006", "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Sex_body_deficiency_in_Trip13_mutants_/1334375", "title"=>"Sex body deficiency in <i>Trip13</i> mutants.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-13 02:43:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/1947050"], "description"=>"<p>We propose that DSBs induced by SPO11 at the beginning of meiotic prophase are sensed by the MRE11 complex, which activates ATM. ATM inhibits further DSB formation via a feedback loop and promotes DSB repair. ATM activates CHK2, which controls cell cycle progression but is not involved in regulating DSB formation. Recombination progression leads to homologous chromosome synapsis and sex body formation. Besides participating in recombination, TRIP13 is also needed for effective sex body formation. Proper recombination and sex body formation are required to permit meiotic progression.</p>", "links"=>[], "tags"=>["histone variant H 1t", "Trip 13mod arrest", "CHK", "hypomorphic Trip 13 mutation", "compromise meiotic recombination", "spermatocyte arrest", "meiotic DSB repair", "Chk 2 mutants", "MRE 11", "apoptosi", "H 1t stage", "DSB numbers", "aaa", "Nbs 1 hypomorphs", "recombination intermediates", "sex body formation", "response", "mouse spermatocytes result"], "article_id"=>1334376, "categories"=>["Biological Sciences"], "users"=>["Sarai Pacheco", "Marina Marcet-Ortega", "Julian Lange", "Maria Jasin", "Scott Keeney", "Ignasi Roig"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005017.g007", "stats"=>{"downloads"=>0, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Functions_of_the_ATM_signaling_pathway_during_mouse_meiotic_prophase_/1334376", "title"=>"Functions of the ATM signaling pathway during mouse meiotic prophase.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-13 02:43:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/1947104", "https://ndownloader.figshare.com/files/1947105", "https://ndownloader.figshare.com/files/1947106", "https://ndownloader.figshare.com/files/1947108", "https://ndownloader.figshare.com/files/1947109", "https://ndownloader.figshare.com/files/1947110", "https://ndownloader.figshare.com/files/1947111", "https://ndownloader.figshare.com/files/1947112", "https://ndownloader.figshare.com/files/1947113"], "description"=>"<div><p>Most mutations that compromise meiotic recombination or synapsis in mouse spermatocytes result in arrest and apoptosis at the pachytene stage of the first meiotic prophase. Two main mechanisms are thought to trigger arrest: one independent of the double-strand breaks (DSBs) that initiate meiotic recombination, and another activated by persistent recombination intermediates. Mechanisms underlying the recombination-dependent arrest response are not well understood, so we sought to identify factors involved by examining mutants deficient for TRIP13, a conserved AAA+ ATPase required for the completion of meiotic DSB repair. We find that spermatocytes with a hypomorphic <i>Trip13</i> mutation (<i>Trip13<sup>mod/mod</sup></i>) arrest with features characteristic of early pachynema in wild type, namely, fully synapsed chromosomes without incorporation of the histone variant H1t into chromatin. These cells then undergo apoptosis, possibly in response to the arrest or in response to a defect in sex body formation. However, TRIP13-deficient cells that additionally lack the DSB-responsive kinase ATM progress further, reaching an H1t-positive stage (i.e., similar to mid/late pachynema in wild type) despite the presence of unrepaired DSBs. TRIP13-deficient spermatocytes also progress to an H1t-positive stage if ATM activity is attenuated by hypomorphic mutations in <i>Mre11</i> or <i>Nbs1</i> or by elimination of the ATM-effector kinase CHK2. These mutant backgrounds nonetheless experience an apoptotic block to further spermatogenic progression, most likely caused by failure to form a sex body. DSB numbers are elevated in <i>Mre11</i> and <i>Nbs1</i> hypomorphs but not <i>Chk2</i> mutants, thus delineating genetic requirements for the ATM-dependent negative feedback loop that regulates DSB numbers. The findings demonstrate for the first time that ATM-dependent signaling enforces the normal pachytene response to persistent recombination intermediates. Our work supports the conclusion that recombination defects trigger spermatocyte arrest via pathways than are genetically distinct from sex body failure-promoted apoptosis and confirm that the latter can function even when recombination-dependent arrest is inoperative. Implications of these findings for understanding the complex relationships between spermatocyte arrest and apoptosis are discussed.</p></div>", "links"=>[], "tags"=>["histone variant H 1t", "Trip 13mod arrest", "CHK", "hypomorphic Trip 13 mutation", "compromise meiotic recombination", "spermatocyte arrest", "meiotic DSB repair", "Chk 2 mutants", "MRE 11", "apoptosi", "H 1t stage", "DSB numbers", "aaa", "Nbs 1 hypomorphs", "recombination intermediates", "sex body formation", "response", "mouse spermatocytes result"], "article_id"=>1334420, "categories"=>["Biological Sciences"], "users"=>["Sarai Pacheco", "Marina Marcet-Ortega", "Julian Lange", "Maria Jasin", "Scott Keeney", "Ignasi Roig"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1005017.s001", "https://dx.doi.org/10.1371/journal.pgen.1005017.s002", "https://dx.doi.org/10.1371/journal.pgen.1005017.s003", "https://dx.doi.org/10.1371/journal.pgen.1005017.s004", "https://dx.doi.org/10.1371/journal.pgen.1005017.s005", "https://dx.doi.org/10.1371/journal.pgen.1005017.s006", "https://dx.doi.org/10.1371/journal.pgen.1005017.s007", "https://dx.doi.org/10.1371/journal.pgen.1005017.s008", "https://dx.doi.org/10.1371/journal.pgen.1005017.s009"], "stats"=>{"downloads"=>3, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_ATM_Signaling_Cascade_Promotes_Recombination_Dependent_Pachytene_Arrest_in_Mouse_Spermatocytes_/1334420", "title"=>"The ATM Signaling Cascade Promotes Recombination-Dependent Pachytene Arrest in Mouse Spermatocytes", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-03-13 02:43:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/1947045"], "description"=>"<p>(A-B) Cross-sections of <i>Chk2</i><sup>−/−</sup> and <i>Trip13</i><sup><i>mod/mod</i></sup><i>Chk2</i><sup>−/−</sup> testes stained with PAS-Haematoxylin. <i>Chk2</i><sup>−/−</sup> testes contained all spermatogenic cell types, whereas <i>Trip13</i><sup><i>mod/mod</i></sup><i>Chk2</i><sup>−/−</sup> spermatocytes arrested in tubules at epithelial stage IV (red arrowhead). Note the presence of spermatids (green arrowhead) indicating that some <i>Trip13</i><sup><i>mod/mod</i></sup><i>Chk2</i><sup>−/−</sup> cells manage to complete meiosis. (C-F) Early and mid/late pachytene <i>Trip13</i><sup><i>mod/mod</i></sup><i>Chk2</i><sup>−/−</sup> spermatocytes stained for H1t, γH2AX, and SYCP3. Both early and mid/late pachytene cells exhibit multiple γH2AX patches (arrowheads) corresponding to unrepaired DSBs, as well as accumulation of γH2AX on the chromatin of the sex chromosomes (arrows). (G) Quantification of the number of γH2AX patches in <i>Trip13</i><sup><i>mod/mod</i></sup><i>Chk2</i><sup>−/−</sup> spermatocytes. Data for wild type, <i>Trip13</i><sup><i>mod/mod</i></sup> and <i>Spo11</i><sup><i>+/−</i></sup><i>Atm</i><sup>−/−</sup> reproduced from <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005017#pgen.1005017.g001\" target=\"_blank\">Fig. 1D</a> for comparison, N shows the total number of cells counted per each stage and genotype. (H) γH2AX patches in diplotene cells. The plot on the left shows the number of γH2AX patches per cell. Note that overplotting of zero values obscures information about proportions of cells that lack a γH2AX patch, so the plot on the right displays proportions of cells with or without a γH2AX patch. Primary data for panels G and H are provided in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005017#pgen.1005017.s009\" target=\"_blank\">S1 Dataset</a>. N shows the total number of cells counted per each stage and genotype. Bar in (A) represents 20 μm and applies to panels (A-B). Bar in (D) represents 10 μm and applies to panels (C-F).</p>", "links"=>[], "tags"=>["histone variant H 1t", "Trip 13mod arrest", "CHK", "hypomorphic Trip 13 mutation", "compromise meiotic recombination", "spermatocyte arrest", "meiotic DSB repair", "Chk 2 mutants", "MRE 11", "apoptosi", "H 1t stage", "DSB numbers", "aaa", "Nbs 1 hypomorphs", "recombination intermediates", "sex body formation", "response", "mouse spermatocytes result"], "article_id"=>1334371, "categories"=>["Biological Sciences"], "users"=>["Sarai Pacheco", "Marina Marcet-Ortega", "Julian Lange", "Maria Jasin", "Scott Keeney", "Ignasi Roig"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005017.g005", "stats"=>{"downloads"=>1, "page_views"=>108, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CHK2_is_required_to_maintain_early_pachytene_arrest_caused_by_TRIP13_deficiency_/1334371", "title"=>"CHK2 is required to maintain early pachytene arrest caused by TRIP13 deficiency.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-13 02:43:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/1947026"], "description"=>"<p>(A-D) Testis cross-sections showing individual seminiferous tubules from the indicated genotypes, stained with PAS-Haematoxylin. (A) In wild type, spermatogonia, spermatocytes and spermatids are present. (B) Stage IV tubule in <i>Trip13</i><sup><i>mod/mod</i></sup> with apoptotic spermatocytes, corresponding to pachynema (red arrowhead) [<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005017#pgen.1005017.ref022\" target=\"_blank\">22</a>,<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005017#pgen.1005017.ref023\" target=\"_blank\">23</a>]. Only a minor fraction of cells complete meiosis (green arrowhead). (C) <i>Spo11</i><sup><i>+/−</i></sup><i>Atm</i><sup>−/−</sup> tubule at stage XII, which is characterized by spermatocytes at metaphase I (red arrowhead) [<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005017#pgen.1005017.ref024\" target=\"_blank\">24</a>]. The presence of lagging chromosomes in some metaphase I spermatocytes is thought to be the cause of apoptosis. Green arrowhead denotes a spermatid that has escaped meiotic arrest. (D) <i>Trip13</i><sup><i>mod/mod</i></sup><i>Spo11</i><sup><i>+/−</i></sup><i>Atm</i><sup>−/−</sup> tubule at stage IV, presenting multiple apoptotic spermatocytes at pachytene stage (red arrowhead). No spermatids were observed. (E-H) Two <i>Trip13</i><sup><i>mod/mod</i></sup><i>Spo11</i><sup><i>+/−</i></sup><i>Atm</i><sup>−/−</sup> spermatocytes, one at preleptonema (left) and the other at mid/late pachynema (right), stained for H1t (blue, F), γH2AX (red, G) and SYCP3 (green, H). A high degree of asynapsis occurs in the H1t-positive cell, where long stretches of axial elements are visible (arrowhead). (I) Enlarged image of a bivalent that has successfully synapsed only a portion of the homologous chromosome pair (arrow). (J) Number of γH2AX patches in mid/late pachytene spermatocytes of the indicated genotypes. Triple and double mutants that generate more DSBs and fail to complete synapsis (highlighted in dark grey) display more γH2AX patches at mid/late pachynema than <i>Trip13</i><sup><i>mod/mod</i></sup><i>Chk2</i><sup>−/−</sup> cells (highlighted in light grey). Data for wild type, <i>Trip13</i><sup><i>mod/mod</i></sup> and <i>Spo11</i><sup><i>+/−</i></sup><i>Atm</i><sup>−/−</sup> reproduced from <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005017#pgen.1005017.g001\" target=\"_blank\">Fig. 1D</a> for comparison. N shows the total number of cells counted per each genotype. Asterisk marks statistically significant differences compared to <i>Trip13</i><sup><i>mod/mod</i></sup>, P≤0.0001, t test. Primary data are provided in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005017#pgen.1005017.s009\" target=\"_blank\">S1 Dataset</a>. Bar in (A) represents 20 μm and applies to panels (A-D). Bar in (H) represents 10 μm and applies to panels (E-H).</p>", "links"=>[], "tags"=>["histone variant H 1t", "Trip 13mod arrest", "CHK", "hypomorphic Trip 13 mutation", "compromise meiotic recombination", "spermatocyte arrest", "meiotic DSB repair", "Chk 2 mutants", "MRE 11", "apoptosi", "H 1t stage", "DSB numbers", "aaa", "Nbs 1 hypomorphs", "recombination intermediates", "sex body formation", "response", "mouse spermatocytes result"], "article_id"=>1334356, "categories"=>["Biological Sciences"], "users"=>["Sarai Pacheco", "Marina Marcet-Ortega", "Julian Lange", "Maria Jasin", "Scott Keeney", "Ignasi Roig"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005017.g002", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Trip13_mod_mod_Spo11_8722_Atm_8722_8722_spermatocytes_arrest_at_epithelial_stage_IV_but_present_autosomal_asynapsis_multiple_unrepaired_DSBs_and_fail_to_form_a_sex_body_at_mid_late_pachynema_/1334356", "title"=>"<i>Trip13</i><sup><i>mod/mod</i></sup><i>Spo11</i><sup><i>+/−</i></sup><i>Atm</i><sup>−/−</sup> spermatocytes arrest at epithelial stage IV, but present autosomal asynapsis, multiple unrepaired DSBs and fail to form a sex body at mid/late pachynema.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-13 02:43:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/1947021"], "description"=>"<p>(A) Apoptotic <i>Trip13</i><sup><i>mod/mod</i></sup> spermatocyte showing the axial element protein SYCP3 (green), TUNEL (green), mid/late pachytene stage marker H1t (blue) and γH2AX staining (red). Absence of H1t staining (blue) in the TUNEL-positive cell indicates that this is an early pachytene stage spermatocyte. (B) TUNEL staining appears as pan-nuclear labelling that overlaps all chromatin, which is observed in only a fraction of the analysed cells (asterisk shows an adjacent TUNEL-negative cell). (C) γH2AX localizes to the sex body (arrow) and unrepaired breaks (arrowheads). (D) Number of autosomal γH2AX patches (similar to arrowheads in (C)) counted in H1t-negative (early) and H1t-positive (mid/late) pachytene and diplotene cells from animals of the indicated genotypes. Means are indicated with horizontal lines. N shows the total number of cells counted per each stage and genotype. Primary data are provided in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005017#pgen.1005017.s009\" target=\"_blank\">S1 Dataset</a>. (E-P) Representative cells from the indicated genotypes stained for H1t (blue), γH2AX (red) and SYCP3 (green). In <i>Trip13</i><sup><i>mod/mod</i></sup>, mid/late pachytene cells have substantially fewer γH2AX patches than early pachytene spermatocytes. Bar in (C) represents 10 μm and applies to all panels.</p>", "links"=>[], "tags"=>["histone variant H 1t", "Trip 13mod arrest", "CHK", "hypomorphic Trip 13 mutation", "compromise meiotic recombination", "spermatocyte arrest", "meiotic DSB repair", "Chk 2 mutants", "MRE 11", "apoptosi", "H 1t stage", "DSB numbers", "aaa", "Nbs 1 hypomorphs", "recombination intermediates", "sex body formation", "response", "mouse spermatocytes result"], "article_id"=>1334351, "categories"=>["Biological Sciences"], "users"=>["Sarai Pacheco", "Marina Marcet-Ortega", "Julian Lange", "Maria Jasin", "Scott Keeney", "Ignasi Roig"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005017.g001", "stats"=>{"downloads"=>0, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Trip13_mod_mod_spermatocytes_activate_a_recombination_dependent_arrest_at_pachynema_/1334351", "title"=>"<i>Trip13</i><sup><i>mod/mod</i></sup> spermatocytes activate a recombination-dependent arrest at pachynema.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-13 02:43:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/1947030"], "description"=>"<p>(A-B) Cross sections of <i>Nbs1</i><sup><i>ΔB/ΔB</i></sup> and <i>Trip13</i><sup><i>mod/mod</i></sup><i>Nbs1</i><sup><i>ΔB/ΔB</i></sup> stage IV tubules stained with PAS-Haematoxylin. (C-D) Early (C) and mid/late (D) pachytene <i>Trip13</i><sup><i>mod/mod</i></sup><i>Nbs1</i><sup><i>ΔB/ΔB</i></sup> spermatocytes stained for H1t, γH2AX, and SYCP3. Both cells present multiple unrepaired DSBs and incomplete synapsis. Bar in (A) represents 20 μm and applies to panels (A-B). Bar in (D) represents 10 μm and applies to panels (C-D).</p>", "links"=>[], "tags"=>["histone variant H 1t", "Trip 13mod arrest", "CHK", "hypomorphic Trip 13 mutation", "compromise meiotic recombination", "spermatocyte arrest", "meiotic DSB repair", "Chk 2 mutants", "MRE 11", "apoptosi", "H 1t stage", "DSB numbers", "aaa", "Nbs 1 hypomorphs", "recombination intermediates", "sex body formation", "response", "mouse spermatocytes result"], "article_id"=>1334360, "categories"=>["Biological Sciences"], "users"=>["Sarai Pacheco", "Marina Marcet-Ortega", "Julian Lange", "Maria Jasin", "Scott Keeney", "Ignasi Roig"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005017.g003", "stats"=>{"downloads"=>0, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Trip13_mod_mod_Nbs1_916_B_916_B_spermatocytes_arrest_in_mid_late_pachynema_with_unrepaired_DSBs_at_epithelial_stage_IV_/1334360", "title"=>"<i>Trip13</i><sup><i>mod/mod</i></sup><i>Nbs1</i><sup><i>ΔB/ΔB</i></sup> spermatocytes arrest in mid/late pachynema with unrepaired DSBs at epithelial stage IV.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-03-13 02:43:08"}

PMC Usage Stats | Further Information

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{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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