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Autophagy induction on impaired spermatogenesis of xeroderma pigmentosum group A gene-deficient mice
Hironobu Nakane1, Katsumi Higaki2, Yuka Koyama1
1Department of Anatomy, Faculty of Medicine, Tottori University.
Abstract:
Xeroderma pigmentosum (XP) involves a defect in the initial step of nucleotide excision repair (NER) and consists of eight genetic complementation groups (groups A-G and a variant). XP group A (XPA) patients have a high incidence of UV-induced skin tumors, immature testicular development, and neurological symptoms. In an earlier study, we have shown that XP group A (Xpa) gene-knockout mice (Xpa-/- mice) were highly sensitive to UV-induced skin carcinogenesis with a defect in NER and were highly susceptibility to spontaneous tumorigenesis with impaired spermatogenesis. However, the pathology of impaired spermatogenesis in Xpa-/- mice is unknown. To unravel the underlying pathology, we made a concerted effort using the testis of 3-month-old Xpa-/- mice. We found many large vacuoles in the seminiferous tubules of 3-month old Xpa-/- mice, while there were no large vacuoles in that of Xpa+/+ mice. Immunohistochemistry of microtubule-associated protein 1 light chain 3 (LC3), an autophagosome marker, showed degenerating cells with intense signal of LC3 in the seminiferous tubules, and immunoblotting revealed induction of LC3-II in the 3-month-old Xpa-/- mice. The results of the present study suggest autophagy induction as the possible mechanism underlying the impaired spermatogenesis in Xpa-/- mice. Therefore, Xpa-/- mice could be a useful model for investigating aging and male infertility with low expression of XPA.
Insights
Xeroderma pigmentosum group A (XPA) impairs male fertility in mice. Autophagy induction in seminiferous tubules is the likely cause of impaired spermatogenesis in XPA-deficient mice.
Area of Science:
- Genetics
- Cell Biology
- Reproductive Biology
Background:
- Xeroderma pigmentosum (XP) is a genetic disorder characterized by defective nucleotide excision repair (NER), leading to increased cancer risk and developmental issues.
- XP group A (XPA) patients exhibit high rates of UV-induced skin tumors, neurological symptoms, and impaired testicular development.
- Xpa gene-knockout mice (Xpa-/-) show UV sensitivity, spontaneous tumorigenesis, and impaired spermatogenesis, but the underlying pathology is unclear.
Purpose of the Study:
- To investigate the pathological mechanism of impaired spermatogenesis in Xpa-/- mice.
- To explore the role of autophagy in the observed testicular dysfunction.
Main Methods:
- Histological examination of seminiferous tubules in 3-month-old Xpa-/- and Xpa+/+ mice.
- Immunohistochemistry using microtubule-associated protein 1 light chain 3 (LC3) as an autophagosome marker.
- Immunoblotting to detect LC3-II levels.
Main Results:
- Xpa-/- mice exhibited large vacuoles in seminiferous tubules, absent in Xpa+/+ mice.
- Immunohistochemistry revealed degenerating cells with strong LC3 signals in Xpa-/- seminiferous tubules.
- Immunoblotting confirmed increased LC3-II levels in Xpa-/- mice, indicating autophagy induction.
Conclusions:
- Autophagy induction is a potential mechanism underlying impaired spermatogenesis in Xpa-/- mice.
- Xpa-/- mice serve as a valuable model for studying aging and male infertility associated with low XPA expression.
