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Mutations in Caenorhabditis elegans him-19 show meiotic defects that worsen with age.

Tang L, Machacek T, Mamnun YM, Penkner A, Gloggnitzer J, Wegrostek C, Konrat R, Jantsch MF, Loidl J, Jantsch V - Mol. Biol. Cell (2010)

Bottom Line: Mutant him-19(jf6) animals show a reduction in pairing of homologous chromosomes and subsequent bivalent formation.Ultimately, mutation of him-19 leads to chromosome missegregation and reduced offspring viability.Further characterization of him-19 could contribute to our understanding of age-dependent meiotic defects in humans.

View Article: PubMed Central - PubMed

Affiliation: Department of Chromosome Biology, Max F. Perutz Laboratories, University of Vienna, A-1030 Vienna, Austria.

ABSTRACT
From a screen for meiotic Caenorhabditis elegans mutants based on high incidence of males, we identified a novel gene, him-19, with multiple functions in prophase of meiosis I. Mutant him-19(jf6) animals show a reduction in pairing of homologous chromosomes and subsequent bivalent formation. Consistently, synaptonemal complex formation is spatially restricted and possibly involves nonhomologous chromosomes. Also, foci of the recombination protein RAD-51 occur delayed or cease altogether. Ultimately, mutation of him-19 leads to chromosome missegregation and reduced offspring viability. The observed defects suggest that HIM-19 is important for both homology recognition and formation of meiotic DNA double-strand breaks. It therefore seems to be engaged in an early meiotic event, resembling in this respect the regulator kinase CHK-2. Most astonishingly, him-19(jf6) hermaphrodites display worsening of phenotypes with increasing age, whereas defects are more severe in female than in male meiosis. This finding is consistent with depletion of a him-19-dependent factor during the production of oocytes. Further characterization of him-19 could contribute to our understanding of age-dependent meiotic defects in humans.

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Aging phenotype of the him-19(jf6) mutant. (A) Graph illustrates the percentages of hatch rate (y-axis) of the assorted strains counted over the reproductive time span (x-axis). Fewer eggs hatched in the later broods in the mutant and in wild type worms injected with DNA encoding Y95B8A.11 leading to transgene-mediated gene silencing (cosuppression). Crosses of wild-type females with him-19(jf6) males are less affected than crosses performed with him-19(jf6) females or self crosses. Viability of the offspring of prom-1(ok1120) or chk-2(gk212) remained steadily low over the time frame investigated. Gray lines in bars for prom-1 and chk-2 indicate the 95% confidence intervals. Detailed numbers of brood size and hatch rates for each time point are shown in Supplemental Table 1. (B) Graph describes the percentage of male progeny (y-axis) in various broods (x-axis). At 20°C, the him-19(jf6) hermaphrodites had 12.87% of male progeny on day 1 (n = 171), 21.67% on day 2 (n = 180), and 50.0% on day 3 (n = 24). At 25°C, the him-19(jf6) hermaphrodites had 4.11% of male progeny on day 1 (n = 243), 25.22% on day 2 (n = 115), and 50.0% on day 3 (n = 6).
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Figure 2: Aging phenotype of the him-19(jf6) mutant. (A) Graph illustrates the percentages of hatch rate (y-axis) of the assorted strains counted over the reproductive time span (x-axis). Fewer eggs hatched in the later broods in the mutant and in wild type worms injected with DNA encoding Y95B8A.11 leading to transgene-mediated gene silencing (cosuppression). Crosses of wild-type females with him-19(jf6) males are less affected than crosses performed with him-19(jf6) females or self crosses. Viability of the offspring of prom-1(ok1120) or chk-2(gk212) remained steadily low over the time frame investigated. Gray lines in bars for prom-1 and chk-2 indicate the 95% confidence intervals. Detailed numbers of brood size and hatch rates for each time point are shown in Supplemental Table 1. (B) Graph describes the percentage of male progeny (y-axis) in various broods (x-axis). At 20°C, the him-19(jf6) hermaphrodites had 12.87% of male progeny on day 1 (n = 171), 21.67% on day 2 (n = 180), and 50.0% on day 3 (n = 24). At 25°C, the him-19(jf6) hermaphrodites had 4.11% of male progeny on day 1 (n = 243), 25.22% on day 2 (n = 115), and 50.0% on day 3 (n = 6).

Mentions: him-19(jf6) homozygous mutants can be maintained as a stable, homozygous strain. Hence, all studies presented here were performed on homozygous mutant offspring derived from homozygous mutant parents. Embryos hatch at a rate of 18.34% (n = 2094 eggs scored from 11 animals) with a high incidence of males occurring in the surviving progeny (19.01%, which is much higher than the 0.2% natural occurrence found in wild type; Hodgkin et al., 1979). Interestingly, the hatch rate decreases sharply with increasing age of the mother hermaphrodite. Although 51.20% (n = 334) of eggs laid on the first day of the reproduction period successfully hatched; only 16.87% (n = 1067) of eggs hatched from the second day brood; the percentage of hatched eggs dropped further to 4.34% (n = 553) on the third day; and only 6.43% (n = 140) of eggs from the fourth day survived (Figure 2A). As viability decreases, the number of males increases among the hatched animals, consistent with an overall increase in chromosome nondisjunction. On day 1, 12.87% of the progeny produced were males (n = 171); on day 2, 22.16% of the progeny produced were males (n = 176); and 50% of the progeny produced were males on day 3 (n = 24; Figure 2B). The deteriorating phenotype observed in the jf6 allele could also be observed in wild-type worms subjected to transgene mediated cosuppression of ORF Y95B8A.11 (Figure 2A). To test whether a similar age-dependent worsening of phenotypes is observed in other meiotic mutants, we scored viability of chk-2 and prom-1 mutants (MacQueen and Villeneuve, 2001; Jantsch et al., 2007). Unlike him-19(jf6), viability of prom-1(ok1140) offspring did not drop with maternal age (Figure 2A). Also, the chk-2(gk212) viability remained steadily low throughout the reproductive span of the mother (Figure 2A). In fact, the 95% confidence intervals might even suggest a slight increase in viability of the offspring with increasing maternal age, at least for prom-1.


Mutations in Caenorhabditis elegans him-19 show meiotic defects that worsen with age.

Tang L, Machacek T, Mamnun YM, Penkner A, Gloggnitzer J, Wegrostek C, Konrat R, Jantsch MF, Loidl J, Jantsch V - Mol. Biol. Cell (2010)

Aging phenotype of the him-19(jf6) mutant. (A) Graph illustrates the percentages of hatch rate (y-axis) of the assorted strains counted over the reproductive time span (x-axis). Fewer eggs hatched in the later broods in the mutant and in wild type worms injected with DNA encoding Y95B8A.11 leading to transgene-mediated gene silencing (cosuppression). Crosses of wild-type females with him-19(jf6) males are less affected than crosses performed with him-19(jf6) females or self crosses. Viability of the offspring of prom-1(ok1120) or chk-2(gk212) remained steadily low over the time frame investigated. Gray lines in bars for prom-1 and chk-2 indicate the 95% confidence intervals. Detailed numbers of brood size and hatch rates for each time point are shown in Supplemental Table 1. (B) Graph describes the percentage of male progeny (y-axis) in various broods (x-axis). At 20°C, the him-19(jf6) hermaphrodites had 12.87% of male progeny on day 1 (n = 171), 21.67% on day 2 (n = 180), and 50.0% on day 3 (n = 24). At 25°C, the him-19(jf6) hermaphrodites had 4.11% of male progeny on day 1 (n = 243), 25.22% on day 2 (n = 115), and 50.0% on day 3 (n = 6).
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Figure 2: Aging phenotype of the him-19(jf6) mutant. (A) Graph illustrates the percentages of hatch rate (y-axis) of the assorted strains counted over the reproductive time span (x-axis). Fewer eggs hatched in the later broods in the mutant and in wild type worms injected with DNA encoding Y95B8A.11 leading to transgene-mediated gene silencing (cosuppression). Crosses of wild-type females with him-19(jf6) males are less affected than crosses performed with him-19(jf6) females or self crosses. Viability of the offspring of prom-1(ok1120) or chk-2(gk212) remained steadily low over the time frame investigated. Gray lines in bars for prom-1 and chk-2 indicate the 95% confidence intervals. Detailed numbers of brood size and hatch rates for each time point are shown in Supplemental Table 1. (B) Graph describes the percentage of male progeny (y-axis) in various broods (x-axis). At 20°C, the him-19(jf6) hermaphrodites had 12.87% of male progeny on day 1 (n = 171), 21.67% on day 2 (n = 180), and 50.0% on day 3 (n = 24). At 25°C, the him-19(jf6) hermaphrodites had 4.11% of male progeny on day 1 (n = 243), 25.22% on day 2 (n = 115), and 50.0% on day 3 (n = 6).
Mentions: him-19(jf6) homozygous mutants can be maintained as a stable, homozygous strain. Hence, all studies presented here were performed on homozygous mutant offspring derived from homozygous mutant parents. Embryos hatch at a rate of 18.34% (n = 2094 eggs scored from 11 animals) with a high incidence of males occurring in the surviving progeny (19.01%, which is much higher than the 0.2% natural occurrence found in wild type; Hodgkin et al., 1979). Interestingly, the hatch rate decreases sharply with increasing age of the mother hermaphrodite. Although 51.20% (n = 334) of eggs laid on the first day of the reproduction period successfully hatched; only 16.87% (n = 1067) of eggs hatched from the second day brood; the percentage of hatched eggs dropped further to 4.34% (n = 553) on the third day; and only 6.43% (n = 140) of eggs from the fourth day survived (Figure 2A). As viability decreases, the number of males increases among the hatched animals, consistent with an overall increase in chromosome nondisjunction. On day 1, 12.87% of the progeny produced were males (n = 171); on day 2, 22.16% of the progeny produced were males (n = 176); and 50% of the progeny produced were males on day 3 (n = 24; Figure 2B). The deteriorating phenotype observed in the jf6 allele could also be observed in wild-type worms subjected to transgene mediated cosuppression of ORF Y95B8A.11 (Figure 2A). To test whether a similar age-dependent worsening of phenotypes is observed in other meiotic mutants, we scored viability of chk-2 and prom-1 mutants (MacQueen and Villeneuve, 2001; Jantsch et al., 2007). Unlike him-19(jf6), viability of prom-1(ok1140) offspring did not drop with maternal age (Figure 2A). Also, the chk-2(gk212) viability remained steadily low throughout the reproductive span of the mother (Figure 2A). In fact, the 95% confidence intervals might even suggest a slight increase in viability of the offspring with increasing maternal age, at least for prom-1.

Bottom Line: Mutant him-19(jf6) animals show a reduction in pairing of homologous chromosomes and subsequent bivalent formation.Ultimately, mutation of him-19 leads to chromosome missegregation and reduced offspring viability.Further characterization of him-19 could contribute to our understanding of age-dependent meiotic defects in humans.

View Article: PubMed Central - PubMed

Affiliation: Department of Chromosome Biology, Max F. Perutz Laboratories, University of Vienna, A-1030 Vienna, Austria.

ABSTRACT
From a screen for meiotic Caenorhabditis elegans mutants based on high incidence of males, we identified a novel gene, him-19, with multiple functions in prophase of meiosis I. Mutant him-19(jf6) animals show a reduction in pairing of homologous chromosomes and subsequent bivalent formation. Consistently, synaptonemal complex formation is spatially restricted and possibly involves nonhomologous chromosomes. Also, foci of the recombination protein RAD-51 occur delayed or cease altogether. Ultimately, mutation of him-19 leads to chromosome missegregation and reduced offspring viability. The observed defects suggest that HIM-19 is important for both homology recognition and formation of meiotic DNA double-strand breaks. It therefore seems to be engaged in an early meiotic event, resembling in this respect the regulator kinase CHK-2. Most astonishingly, him-19(jf6) hermaphrodites display worsening of phenotypes with increasing age, whereas defects are more severe in female than in male meiosis. This finding is consistent with depletion of a him-19-dependent factor during the production of oocytes. Further characterization of him-19 could contribute to our understanding of age-dependent meiotic defects in humans.

Show MeSH
Related in: MedlinePlus