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Fanconi anemia signaling and Mus81 cooperate to safeguard development and crosslink repair.

Larin M, Gallo D, Tamblyn L, Yang J, Liao H, Sabat N, Brown GW, McPherson JP - Nucleic Acids Res. (2014)

Bottom Line: Individuals with Fanconi anemia (FA) are susceptible to bone marrow failure, congenital abnormalities, cancer predisposition and exhibit defective DNA crosslink repair.This cooperativity of FancC and Mus81 in developmental outcome was also mirrored in response to crosslink damage and chromosomal integrity.Thus, our findings reveal that both pathways safeguard against DNA damage from exceeding a critical threshold that triggers proliferation arrest and apoptosis, leading to compromised in utero development.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, M5S 1A8, Canada.

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Increased embryonic lethality and growth delay in FkoMko mice. (a) Percentage of observed/expected FkoMko, Fko and Mko embryos/embryonic day (solid line) and projected survival (dashed line). (b) Representative images of developmental delays in FkoMko embryos at E9.5 and E10.5. Arrowhead, microcephaly. (c) Growth delay in FkoMko mice compared to sibling FhetMhet mice at 2 weeks of age. (d) Growth delay in FkoMko mice compared to sibling FhetMhet mice at 6 weeks of age. (e) Mass of female and male FhetMhet, FhetMko, FkoMhet and FkoMko mice at 4 weeks of age. Open circles represent each mouse assessed, solid circles represent mean mass for each group. Error bars represent ± standard deviation (SD), n values on the x-axis denote sample sizes. For the female cohort, ***P < 0.001 for FkoMko versus all genotypes by one-way ANOVA followed by Holm–Sidak post hoc test. For the male cohort, †P < 0.05 FkoMko versus FhetMhet or FhetMko by one-way ANOVA on ranks followed by Dunn's post hoc test.
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Figure 1: Increased embryonic lethality and growth delay in FkoMko mice. (a) Percentage of observed/expected FkoMko, Fko and Mko embryos/embryonic day (solid line) and projected survival (dashed line). (b) Representative images of developmental delays in FkoMko embryos at E9.5 and E10.5. Arrowhead, microcephaly. (c) Growth delay in FkoMko mice compared to sibling FhetMhet mice at 2 weeks of age. (d) Growth delay in FkoMko mice compared to sibling FhetMhet mice at 6 weeks of age. (e) Mass of female and male FhetMhet, FhetMko, FkoMhet and FkoMko mice at 4 weeks of age. Open circles represent each mouse assessed, solid circles represent mean mass for each group. Error bars represent ± standard deviation (SD), n values on the x-axis denote sample sizes. For the female cohort, ***P < 0.001 for FkoMko versus all genotypes by one-way ANOVA followed by Holm–Sidak post hoc test. For the male cohort, †P < 0.05 FkoMko versus FhetMhet or FhetMko by one-way ANOVA on ranks followed by Dunn's post hoc test.

Mentions: To query a possible interaction between the FA pathway and Mus81 in vivo, FhetMko mice or FhetMhet mice were intercrossed to obtain mice deficient in both FancC and Mus81. Of the 270 offspring resulting from FhetMko × FhetMhet crosses, 26 FkoMko mice were expected but only nine were observed at birth, indicating significant in utero lethality (P < 0.005, χ2 test; Supplementary Table S1). Of the 245 offspring obtained from FhetMko × FhetMko crosses, 61 FkoMko mice were expected but only 25 FkoMko mice were obtained at birth, also indicative of embryonic lethality (P < 0.005, χ2 test). The percentage of observed/expected FkoMko mice at birth for both crosses was 35% and 41%, respectively, indicative of a greater susceptibility to death in utero than Fko mice (61% observed/expected; Supplementary Table SI). Recovery of viable embryos from E9.5 and earlier revealed that FkoMko embryos were present and viable at the expected Mendelian ratio, but a drastic decline in viable FkoMko embryos occurred between E10.5 and E12.5 (from 79% observed/expected at E9.5 to 40% by E12.5) compared to Fko embryos (from 67% observed/expected at E9.5 to 62.5% by E12.5; Figure 1A and Supplementary Table S1). Unlike Fko embryos, FkoMko embryos appear particularly susceptible to death during this developmental period. When we examined littermates between E9.5 and E11.5, viable FkoMko embryos exhibited a greater incidence of delays in growth and development, an effect particularly prevalent in the head region (Figure 1B and Supplementary Table S2). The growth defect observed in FkoMko embryos was also evident in live-born mice (Figure 1C–E). Mass of FkoMko mice and sibling controls was measured on days 10, 21, 28, 42 and 56. Both male and female FkoMko mice at day 28 were smaller in size and mass than Fko, Mko or littermate controls (Figure 1E).


Fanconi anemia signaling and Mus81 cooperate to safeguard development and crosslink repair.

Larin M, Gallo D, Tamblyn L, Yang J, Liao H, Sabat N, Brown GW, McPherson JP - Nucleic Acids Res. (2014)

Increased embryonic lethality and growth delay in FkoMko mice. (a) Percentage of observed/expected FkoMko, Fko and Mko embryos/embryonic day (solid line) and projected survival (dashed line). (b) Representative images of developmental delays in FkoMko embryos at E9.5 and E10.5. Arrowhead, microcephaly. (c) Growth delay in FkoMko mice compared to sibling FhetMhet mice at 2 weeks of age. (d) Growth delay in FkoMko mice compared to sibling FhetMhet mice at 6 weeks of age. (e) Mass of female and male FhetMhet, FhetMko, FkoMhet and FkoMko mice at 4 weeks of age. Open circles represent each mouse assessed, solid circles represent mean mass for each group. Error bars represent ± standard deviation (SD), n values on the x-axis denote sample sizes. For the female cohort, ***P < 0.001 for FkoMko versus all genotypes by one-way ANOVA followed by Holm–Sidak post hoc test. For the male cohort, †P < 0.05 FkoMko versus FhetMhet or FhetMko by one-way ANOVA on ranks followed by Dunn's post hoc test.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Figure 1: Increased embryonic lethality and growth delay in FkoMko mice. (a) Percentage of observed/expected FkoMko, Fko and Mko embryos/embryonic day (solid line) and projected survival (dashed line). (b) Representative images of developmental delays in FkoMko embryos at E9.5 and E10.5. Arrowhead, microcephaly. (c) Growth delay in FkoMko mice compared to sibling FhetMhet mice at 2 weeks of age. (d) Growth delay in FkoMko mice compared to sibling FhetMhet mice at 6 weeks of age. (e) Mass of female and male FhetMhet, FhetMko, FkoMhet and FkoMko mice at 4 weeks of age. Open circles represent each mouse assessed, solid circles represent mean mass for each group. Error bars represent ± standard deviation (SD), n values on the x-axis denote sample sizes. For the female cohort, ***P < 0.001 for FkoMko versus all genotypes by one-way ANOVA followed by Holm–Sidak post hoc test. For the male cohort, †P < 0.05 FkoMko versus FhetMhet or FhetMko by one-way ANOVA on ranks followed by Dunn's post hoc test.
Mentions: To query a possible interaction between the FA pathway and Mus81 in vivo, FhetMko mice or FhetMhet mice were intercrossed to obtain mice deficient in both FancC and Mus81. Of the 270 offspring resulting from FhetMko × FhetMhet crosses, 26 FkoMko mice were expected but only nine were observed at birth, indicating significant in utero lethality (P < 0.005, χ2 test; Supplementary Table S1). Of the 245 offspring obtained from FhetMko × FhetMko crosses, 61 FkoMko mice were expected but only 25 FkoMko mice were obtained at birth, also indicative of embryonic lethality (P < 0.005, χ2 test). The percentage of observed/expected FkoMko mice at birth for both crosses was 35% and 41%, respectively, indicative of a greater susceptibility to death in utero than Fko mice (61% observed/expected; Supplementary Table SI). Recovery of viable embryos from E9.5 and earlier revealed that FkoMko embryos were present and viable at the expected Mendelian ratio, but a drastic decline in viable FkoMko embryos occurred between E10.5 and E12.5 (from 79% observed/expected at E9.5 to 40% by E12.5) compared to Fko embryos (from 67% observed/expected at E9.5 to 62.5% by E12.5; Figure 1A and Supplementary Table S1). Unlike Fko embryos, FkoMko embryos appear particularly susceptible to death during this developmental period. When we examined littermates between E9.5 and E11.5, viable FkoMko embryos exhibited a greater incidence of delays in growth and development, an effect particularly prevalent in the head region (Figure 1B and Supplementary Table S2). The growth defect observed in FkoMko embryos was also evident in live-born mice (Figure 1C–E). Mass of FkoMko mice and sibling controls was measured on days 10, 21, 28, 42 and 56. Both male and female FkoMko mice at day 28 were smaller in size and mass than Fko, Mko or littermate controls (Figure 1E).

Bottom Line: Individuals with Fanconi anemia (FA) are susceptible to bone marrow failure, congenital abnormalities, cancer predisposition and exhibit defective DNA crosslink repair.This cooperativity of FancC and Mus81 in developmental outcome was also mirrored in response to crosslink damage and chromosomal integrity.Thus, our findings reveal that both pathways safeguard against DNA damage from exceeding a critical threshold that triggers proliferation arrest and apoptosis, leading to compromised in utero development.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, M5S 1A8, Canada.

Show MeSH
Related in: MedlinePlus