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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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Meiotic stage distribution in mutant and control spermatocytes.Spermatocyte spreads from 12 d.p.p. (A) and adult mice (B) were stained with SCP3 and SCP1 to analyze SC morphogenesis, and categorized according to meiotic stage. *Other denotes extensively fragmented or otherwise unidentifiable cells.
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pgen-1000042-g003: Meiotic stage distribution in mutant and control spermatocytes.Spermatocyte spreads from 12 d.p.p. (A) and adult mice (B) were stained with SCP3 and SCP1 to analyze SC morphogenesis, and categorized according to meiotic stage. *Other denotes extensively fragmented or otherwise unidentifiable cells.

Mentions: Cytological preparations of Zip4h−/Y spermatocytes were examined for meiotic defects. In contrast to S. cerevisiae zip4 mutants [33], spermatocytes from Zip4h−/Y mice did not exhibit significant perturbations in synaptonemal complex morphogenesis or integrity (Figure 3, Figure S3, and Table S2). There was a subtle increase in percentage of zygotene cells during the semi-synchronous first wave of meiosis in juvenile males (Figure 3A, χ2 = 19.3, P = 0.00024). This same trend was suggested in the asynchronous adult population of spermatocytes, but the difference was not significant (Figure 3B, χ2 = 5.38, P = 0.37). Since pachytene cells forming crossovers always appeared completely synapsed, it appears that although SC morphogenesis is subtly perturbed at early stages of meiosis, this does not prevent cells from ultimately completing synapsis. These results are similar to A. thaliana zip4 mutants in which synapsis initiation appears to be decreased, but the completion of synapsis is not abolished [34].


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)

Meiotic stage distribution in mutant and control spermatocytes.Spermatocyte spreads from 12 d.p.p. (A) and adult mice (B) were stained with SCP3 and SCP1 to analyze SC morphogenesis, and categorized according to meiotic stage. *Other denotes extensively fragmented or otherwise unidentifiable cells.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1000042-g003: Meiotic stage distribution in mutant and control spermatocytes.Spermatocyte spreads from 12 d.p.p. (A) and adult mice (B) were stained with SCP3 and SCP1 to analyze SC morphogenesis, and categorized according to meiotic stage. *Other denotes extensively fragmented or otherwise unidentifiable cells.
Mentions: Cytological preparations of Zip4h−/Y spermatocytes were examined for meiotic defects. In contrast to S. cerevisiae zip4 mutants [33], spermatocytes from Zip4h−/Y mice did not exhibit significant perturbations in synaptonemal complex morphogenesis or integrity (Figure 3, Figure S3, and Table S2). There was a subtle increase in percentage of zygotene cells during the semi-synchronous first wave of meiosis in juvenile males (Figure 3A, χ2 = 19.3, P = 0.00024). This same trend was suggested in the asynchronous adult population of spermatocytes, but the difference was not significant (Figure 3B, χ2 = 5.38, P = 0.37). Since pachytene cells forming crossovers always appeared completely synapsed, it appears that although SC morphogenesis is subtly perturbed at early stages of meiosis, this does not prevent cells from ultimately completing synapsis. These results are similar to A. thaliana zip4 mutants in which synapsis initiation appears to be decreased, but the completion of synapsis is not abolished [34].

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