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Deletion of genes implicated in protecting the integrity of male germ cells has differential effects on the incidence of DNA breaks and germ cell loss.

Paul C, Povey JE, Lawrence NJ, Selfridge J, Melton DW, Saunders PT - PLoS ONE (2007)

Bottom Line: We demonstrate for the first time that depletion of ERCC1 or p53 from germ cells results in an increased incidence of unrepaired DNA breaks in pachytene spermatocytes and increased numbers of caspase-3 positive (apoptotic) germ cells.These data have demonstrated that deletion of Ercc1, Msh2 and p53 can have differential but overlapping affects on germ cell function and sperm production.These findings increase our understanding of the ways in which gene mutations can have an impact on male fertility.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Human Reproductive Sciences Unit, Queen's Medical Research Institute, Edinburgh, United Kingdom.

ABSTRACT

Background: Infertility affects approximately 20% of couples in Europe and in 50% of cases the problem lies with the male partner. The impact of damaged DNA originating in the male germ line on infertility is poorly understood but may increase miscarriage. Mouse models allow us to investigate how deficiencies in DNA repair/damage response pathways impact on formation and function of male germ cells. We have investigated mice with deletions of ERCC1 (excision repair cross-complementing gene 1), MSH2 (MutS homolog 2, involved in mismatch repair pathway), and p53 (tumour suppressor gene implicated in elimination of germ cells with DNA damage).

Principal findings: We demonstrate for the first time that depletion of ERCC1 or p53 from germ cells results in an increased incidence of unrepaired DNA breaks in pachytene spermatocytes and increased numbers of caspase-3 positive (apoptotic) germ cells. Sertoli cell-only tubules were detected in testes from mice lacking expression of ERCC1 or MSH2 but not p53. The number of sperm recovered from epididymes was significantly reduced in mice lacking testicular ERCC1 and 40% of sperm contained DNA breaks whereas the numbers of sperm were not different to controls in adult Msh2 -/- or p53 -/- mice nor did they have significantly compromised DNA.

Conclusions: These data have demonstrated that deletion of Ercc1, Msh2 and p53 can have differential but overlapping affects on germ cell function and sperm production. These findings increase our understanding of the ways in which gene mutations can have an impact on male fertility.

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Related in: MedlinePlus

Histological evaluation of testes from adult mice.Haematoxylin and eosin staining of Ercc1 (A–C), Msh2 (E–G) and p53 (I–K) testes. Sertoli cell only (SCO) tubules are highlighted with asterisks and gaps in testicular epithelium with arrows in TG-Ercc1 −/− (C) and Msh2 −/− (G). Bar = 100 µm. Distribution of seminiferous tubule diameters in D) Ercc1, H) Msh2 and L) p53 lines.
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pone-0000989-g001: Histological evaluation of testes from adult mice.Haematoxylin and eosin staining of Ercc1 (A–C), Msh2 (E–G) and p53 (I–K) testes. Sertoli cell only (SCO) tubules are highlighted with asterisks and gaps in testicular epithelium with arrows in TG-Ercc1 −/− (C) and Msh2 −/− (G). Bar = 100 µm. Distribution of seminiferous tubule diameters in D) Ercc1, H) Msh2 and L) p53 lines.

Mentions: Examination of haematoxylin and eosin stained sections revealed disturbances in testicular architecture in TG-Ercc1 −/− and Msh2 −/− mice compared with control littermates (Figure 1). Consistent with our previous observations [26] TG-Ercc1 −/− testes had reduced numbers of germ cells within the seminiferous tubules and some tubules lacked germ cells altogether (Sertoli cell only, SCO) (Figure 1C, asterisks). All phases of germ cells were observed up to and including mature elongate spermatozoa. A similar, if less pronounced testicular phenotype was observed in the Msh2 −/− testes (Figure 1G, asterisks). In both KOs the presence of tubules with gaps in the seminiferous epithelium were observed (Figure 1 C & G arrows). Mice heterozygous for Msh2 and Ercc1 were comparable to their wild type littermates. Testes from p53 −/− mice appeared normal (Figure 1K).


Deletion of genes implicated in protecting the integrity of male germ cells has differential effects on the incidence of DNA breaks and germ cell loss.

Paul C, Povey JE, Lawrence NJ, Selfridge J, Melton DW, Saunders PT - PLoS ONE (2007)

Histological evaluation of testes from adult mice.Haematoxylin and eosin staining of Ercc1 (A–C), Msh2 (E–G) and p53 (I–K) testes. Sertoli cell only (SCO) tubules are highlighted with asterisks and gaps in testicular epithelium with arrows in TG-Ercc1 −/− (C) and Msh2 −/− (G). Bar = 100 µm. Distribution of seminiferous tubule diameters in D) Ercc1, H) Msh2 and L) p53 lines.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1991594&req=5

pone-0000989-g001: Histological evaluation of testes from adult mice.Haematoxylin and eosin staining of Ercc1 (A–C), Msh2 (E–G) and p53 (I–K) testes. Sertoli cell only (SCO) tubules are highlighted with asterisks and gaps in testicular epithelium with arrows in TG-Ercc1 −/− (C) and Msh2 −/− (G). Bar = 100 µm. Distribution of seminiferous tubule diameters in D) Ercc1, H) Msh2 and L) p53 lines.
Mentions: Examination of haematoxylin and eosin stained sections revealed disturbances in testicular architecture in TG-Ercc1 −/− and Msh2 −/− mice compared with control littermates (Figure 1). Consistent with our previous observations [26] TG-Ercc1 −/− testes had reduced numbers of germ cells within the seminiferous tubules and some tubules lacked germ cells altogether (Sertoli cell only, SCO) (Figure 1C, asterisks). All phases of germ cells were observed up to and including mature elongate spermatozoa. A similar, if less pronounced testicular phenotype was observed in the Msh2 −/− testes (Figure 1G, asterisks). In both KOs the presence of tubules with gaps in the seminiferous epithelium were observed (Figure 1 C & G arrows). Mice heterozygous for Msh2 and Ercc1 were comparable to their wild type littermates. Testes from p53 −/− mice appeared normal (Figure 1K).

Bottom Line: We demonstrate for the first time that depletion of ERCC1 or p53 from germ cells results in an increased incidence of unrepaired DNA breaks in pachytene spermatocytes and increased numbers of caspase-3 positive (apoptotic) germ cells.These data have demonstrated that deletion of Ercc1, Msh2 and p53 can have differential but overlapping affects on germ cell function and sperm production.These findings increase our understanding of the ways in which gene mutations can have an impact on male fertility.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Human Reproductive Sciences Unit, Queen's Medical Research Institute, Edinburgh, United Kingdom.

ABSTRACT

Background: Infertility affects approximately 20% of couples in Europe and in 50% of cases the problem lies with the male partner. The impact of damaged DNA originating in the male germ line on infertility is poorly understood but may increase miscarriage. Mouse models allow us to investigate how deficiencies in DNA repair/damage response pathways impact on formation and function of male germ cells. We have investigated mice with deletions of ERCC1 (excision repair cross-complementing gene 1), MSH2 (MutS homolog 2, involved in mismatch repair pathway), and p53 (tumour suppressor gene implicated in elimination of germ cells with DNA damage).

Principal findings: We demonstrate for the first time that depletion of ERCC1 or p53 from germ cells results in an increased incidence of unrepaired DNA breaks in pachytene spermatocytes and increased numbers of caspase-3 positive (apoptotic) germ cells. Sertoli cell-only tubules were detected in testes from mice lacking expression of ERCC1 or MSH2 but not p53. The number of sperm recovered from epididymes was significantly reduced in mice lacking testicular ERCC1 and 40% of sperm contained DNA breaks whereas the numbers of sperm were not different to controls in adult Msh2 -/- or p53 -/- mice nor did they have significantly compromised DNA.

Conclusions: These data have demonstrated that deletion of Ercc1, Msh2 and p53 can have differential but overlapping affects on germ cell function and sperm production. These findings increase our understanding of the ways in which gene mutations can have an impact on male fertility.

Show MeSH
Related in: MedlinePlus