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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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Increased achiasmate chromosomes in MI cells from Zip4h−/Y mice.Metaphase I spindles from stage XII tubules of Zip4h+/Y (A) and Zip4h−/Y (B) sections. Arrow indicates laggard. Representative diakinesis spreads from a wildtype mouse with no achiasmate chromosomes (C), and a mutant mouse exhibiting achiasmate XY chromosomes (D).
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pgen-1000042-g007: Increased achiasmate chromosomes in MI cells from Zip4h−/Y mice.Metaphase I spindles from stage XII tubules of Zip4h+/Y (A) and Zip4h−/Y (B) sections. Arrow indicates laggard. Representative diakinesis spreads from a wildtype mouse with no achiasmate chromosomes (C), and a mutant mouse exhibiting achiasmate XY chromosomes (D).

Mentions: The decreased crossover frequencies indicated by MLH1 analyses raised the possibility that cells progress to metaphase with non-crossover products. This would in turn lead to univalent chromosomes as a sequela of crossover defects. To test this prediction, MI spindles were examined in histologically stained testis sections. A significant increase in the proportion of Zip4h−/Y spindles exhibiting laggard chromosomes was observed: from 5.6% (11/196) in wildtype, to 12.9% (19/147) in mutants (Figure 7A and 7B; Mantel-Haenszel, M = −2.306, P(one-sided) = 0.010). To determine whether laggards were in fact achiasmate chromosomes, diakinesis spreads were prepared. Zip4h−/Y samples exhibited an increase in both achiasmate XY chromosomes and autosomes (11% and 14%, respectively) compared with controls (1.2% and 9.9%, respectively; Figure 7C and 7D). In total, 25% (18/71) of mutant diakinesis spreads contained achiasmate chromosomes, versus 11% (9/81) of controls (Mantel-Haenszel, M = 2.35, P(one-sided) = 0.0095). These results indicate that reduced crossover formation in Zip4h−/Y spermatocytes results in progression to the MI division in the presence of achiasmate chromosomes.


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)

Increased achiasmate chromosomes in MI cells from Zip4h−/Y mice.Metaphase I spindles from stage XII tubules of Zip4h+/Y (A) and Zip4h−/Y (B) sections. Arrow indicates laggard. Representative diakinesis spreads from a wildtype mouse with no achiasmate chromosomes (C), and a mutant mouse exhibiting achiasmate XY chromosomes (D).
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1000042-g007: Increased achiasmate chromosomes in MI cells from Zip4h−/Y mice.Metaphase I spindles from stage XII tubules of Zip4h+/Y (A) and Zip4h−/Y (B) sections. Arrow indicates laggard. Representative diakinesis spreads from a wildtype mouse with no achiasmate chromosomes (C), and a mutant mouse exhibiting achiasmate XY chromosomes (D).
Mentions: The decreased crossover frequencies indicated by MLH1 analyses raised the possibility that cells progress to metaphase with non-crossover products. This would in turn lead to univalent chromosomes as a sequela of crossover defects. To test this prediction, MI spindles were examined in histologically stained testis sections. A significant increase in the proportion of Zip4h−/Y spindles exhibiting laggard chromosomes was observed: from 5.6% (11/196) in wildtype, to 12.9% (19/147) in mutants (Figure 7A and 7B; Mantel-Haenszel, M = −2.306, P(one-sided) = 0.010). To determine whether laggards were in fact achiasmate chromosomes, diakinesis spreads were prepared. Zip4h−/Y samples exhibited an increase in both achiasmate XY chromosomes and autosomes (11% and 14%, respectively) compared with controls (1.2% and 9.9%, respectively; Figure 7C and 7D). In total, 25% (18/71) of mutant diakinesis spreads contained achiasmate chromosomes, versus 11% (9/81) of controls (Mantel-Haenszel, M = 2.35, P(one-sided) = 0.0095). These results indicate that reduced crossover formation in Zip4h−/Y spermatocytes results in progression to the MI division in the presence of achiasmate chromosomes.

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