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ZIP4H (TEX11) deficiency in the mouse impairs meiotic double strand break repair and the regulation of crossing over.

Adelman CA, Petrini JH - PLoS Genet. (2008)

Bottom Line: As is true for hypomorphic Nbs1 (Nbs1(DeltaB/DeltaB)) mice, Zip4h(-/Y) mutant mice were fertile.Achiasmate chromosomes at the first meiotic division were also observed in Zip4h(-/Y) mutants, consistent with the observed reduction in MLH1 focus formation.These results indicate that meiotic functions of Zip4 family members are conserved and support the view that the Mre11 complex and ZIP4H interact functionally during the execution of the meiotic program in mammals.

View Article: PubMed Central - PubMed

Affiliation: Molecular Biology and Genetics Program, Sloan-Kettering Institute, New York, New York, United States of America.

ABSTRACT
We have recently shown that hypomorphic Mre11 complex mouse mutants exhibit defects in the repair of meiotic double strand breaks (DSBs). This is associated with perturbation of synaptonemal complex morphogenesis, repair and regulation of crossover formation. To further assess the Mre11 complex's role in meiotic progression, we identified testis-specific NBS1-interacting proteins via two-hybrid screening in yeast. In this screen, Zip4h (Tex11), a male germ cell specific X-linked gene was isolated. Based on sequence and predicted structural similarity to the S. cerevisiae and A. thaliana Zip4 orthologs, ZIP4H appears to be the mammalian ortholog. In S. cerevisiae and A. thaliana, Zip4 is a meiosis-specific protein that regulates the level of meiotic crossovers, thus influencing homologous chromosome segregation in these organisms. As is true for hypomorphic Nbs1 (Nbs1(DeltaB/DeltaB)) mice, Zip4h(-/Y) mutant mice were fertile. Analysis of spermatocytes revealed a delay in meiotic double strand break repair and decreased crossover formation as inferred from DMC1 and MLH1 staining patterns, respectively. Achiasmate chromosomes at the first meiotic division were also observed in Zip4h(-/Y) mutants, consistent with the observed reduction in MLH1 focus formation. These results indicate that meiotic functions of Zip4 family members are conserved and support the view that the Mre11 complex and ZIP4H interact functionally during the execution of the meiotic program in mammals.

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Related in: MedlinePlus

Crossover interference is reduced in Zip4h mutants.SC lengths (A) and inter-crossover distance expressed as % of SC (B) of double exchange bivalents in Zip4h+/Y and Zip4h−/Y spermatocytes are graphed according to increasing length. Maximum likelihood fitting of the data to the gamma-distribution allows estimation of the interference parameter, K, for control (C) and mutant (D) double exchange bivalents.
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pgen-1000042-g006: Crossover interference is reduced in Zip4h mutants.SC lengths (A) and inter-crossover distance expressed as % of SC (B) of double exchange bivalents in Zip4h+/Y and Zip4h−/Y spermatocytes are graphed according to increasing length. Maximum likelihood fitting of the data to the gamma-distribution allows estimation of the interference parameter, K, for control (C) and mutant (D) double exchange bivalents.

Mentions: Interference describes the fact that crossovers form non-randomly such that formation of closely spaced crossovers is disfavored [51],[52]. The reduction in crossovers noted in Zip4h−/Y mutants, as well as apparent abolishment of interfering crossovers in S. cerevisiae and A. thaliana zip4 mutants [33],[34] led us to examine crossover interference in Zip4h−/Y mice. Consistent with the observation of reduced crossovers, there were approximately half as many double exchange bivalents in Zip4h−/Y spreads as in Zip4h+/Y (25%±3.3 versus 13%±1.5, respectively). Measurement of SC length and inter-MLH1 distance was carried out on the residual double crossover bivalents (minimum of 137 bivalents per genotype). Since interference can vary between different chromosomes [53], we compared the SC lengths of double exchange bivalents in wildtype and mutants. This comparison demonstrated that SC lengths did not vary as a function of genotype (Figure 6A). The implication of this finding is that the occurrence of double exchange bivalents in Zip4h−/Y spermatocyte spreads is not restricted to a particular SC length class; therefore data describing inter-crossover distances in wild type and Zip4h−/Y are comparable.


ZIP4H (TEX11) deficiency in the mouse impairs meiotic double strand break repair and the regulation of crossing over.

Adelman CA, Petrini JH - PLoS Genet. (2008)

Crossover interference is reduced in Zip4h mutants.SC lengths (A) and inter-crossover distance expressed as % of SC (B) of double exchange bivalents in Zip4h+/Y and Zip4h−/Y spermatocytes are graphed according to increasing length. Maximum likelihood fitting of the data to the gamma-distribution allows estimation of the interference parameter, K, for control (C) and mutant (D) double exchange bivalents.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2267488&req=5

pgen-1000042-g006: Crossover interference is reduced in Zip4h mutants.SC lengths (A) and inter-crossover distance expressed as % of SC (B) of double exchange bivalents in Zip4h+/Y and Zip4h−/Y spermatocytes are graphed according to increasing length. Maximum likelihood fitting of the data to the gamma-distribution allows estimation of the interference parameter, K, for control (C) and mutant (D) double exchange bivalents.
Mentions: Interference describes the fact that crossovers form non-randomly such that formation of closely spaced crossovers is disfavored [51],[52]. The reduction in crossovers noted in Zip4h−/Y mutants, as well as apparent abolishment of interfering crossovers in S. cerevisiae and A. thaliana zip4 mutants [33],[34] led us to examine crossover interference in Zip4h−/Y mice. Consistent with the observation of reduced crossovers, there were approximately half as many double exchange bivalents in Zip4h−/Y spreads as in Zip4h+/Y (25%±3.3 versus 13%±1.5, respectively). Measurement of SC length and inter-MLH1 distance was carried out on the residual double crossover bivalents (minimum of 137 bivalents per genotype). Since interference can vary between different chromosomes [53], we compared the SC lengths of double exchange bivalents in wildtype and mutants. This comparison demonstrated that SC lengths did not vary as a function of genotype (Figure 6A). The implication of this finding is that the occurrence of double exchange bivalents in Zip4h−/Y spermatocyte spreads is not restricted to a particular SC length class; therefore data describing inter-crossover distances in wild type and Zip4h−/Y are comparable.

Bottom Line: As is true for hypomorphic Nbs1 (Nbs1(DeltaB/DeltaB)) mice, Zip4h(-/Y) mutant mice were fertile.Achiasmate chromosomes at the first meiotic division were also observed in Zip4h(-/Y) mutants, consistent with the observed reduction in MLH1 focus formation.These results indicate that meiotic functions of Zip4 family members are conserved and support the view that the Mre11 complex and ZIP4H interact functionally during the execution of the meiotic program in mammals.

View Article: PubMed Central - PubMed

Affiliation: Molecular Biology and Genetics Program, Sloan-Kettering Institute, New York, New York, United States of America.

ABSTRACT
We have recently shown that hypomorphic Mre11 complex mouse mutants exhibit defects in the repair of meiotic double strand breaks (DSBs). This is associated with perturbation of synaptonemal complex morphogenesis, repair and regulation of crossover formation. To further assess the Mre11 complex's role in meiotic progression, we identified testis-specific NBS1-interacting proteins via two-hybrid screening in yeast. In this screen, Zip4h (Tex11), a male germ cell specific X-linked gene was isolated. Based on sequence and predicted structural similarity to the S. cerevisiae and A. thaliana Zip4 orthologs, ZIP4H appears to be the mammalian ortholog. In S. cerevisiae and A. thaliana, Zip4 is a meiosis-specific protein that regulates the level of meiotic crossovers, thus influencing homologous chromosome segregation in these organisms. As is true for hypomorphic Nbs1 (Nbs1(DeltaB/DeltaB)) mice, Zip4h(-/Y) mutant mice were fertile. Analysis of spermatocytes revealed a delay in meiotic double strand break repair and decreased crossover formation as inferred from DMC1 and MLH1 staining patterns, respectively. Achiasmate chromosomes at the first meiotic division were also observed in Zip4h(-/Y) mutants, consistent with the observed reduction in MLH1 focus formation. These results indicate that meiotic functions of Zip4 family members are conserved and support the view that the Mre11 complex and ZIP4H interact functionally during the execution of the meiotic program in mammals.

Show MeSH
Related in: MedlinePlus