title: Rad18 is required for long-term maintenance of spermatogenesis in mouse testes.
abstract: Maintaining the integrity of spermatogenic stem cells is essential to transfer genetic information to a descendant. However, knowledge of maintenance of genetic stability in stem cells is still limited. RAD18 is critical for postreplication repair through mono- and multi-ubiquitination of proliferating cell nuclear antigen (PCNA) to maintain genomic stability. Mammalian RAD18 is highly expressed in the spermatocytes and the nuclei of a few spermatogonia in adult mice. To elucidate the physiological function of RAD18, we analyzed a phenotype of Rad18-/- mice. The mice were born and appeared to grow normally. Although the mice were fertile, fertility and testis weight decreased with age. Histological examination revealed normal spermatogenesis in almost all seminiferous tubules in Rad18-/- testes at 2 months old, and abnormal sperm could not be detected in the epididymis. However, 25% of the tubules lost almost all germ cells at 12 months. The seminiferous tubules frequently retained only late differentiated phase germ cells, suggesting that the exhaustion of spermatogonial stem cells leads to the loss of all germ cells in the seminiferous tubules. Wild-type germ cells were successfully transplanted into and colonized in the seminiferous tubules of aged Rad18-/- mice, indicating that Sertoli cells have a normal supportive function even in aged testes. We conclude that RAD18 is intrinsically required for the long-term maintenance of spermatogenesis.
authors.affiliation: Cell Genetics, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo2-2-1, 860-0811 Kumamoto, Japan.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Sun
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yomogida
authors.forename: Suzu
authors.initials: S
authors.lastname: Sakao
authors.forename: Haruna
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Kayo
authors.initials: K
authors.lastname: Yoshida
authors.forename: Kenji
authors.initials: K
authors.lastname: Watanabe
authors.forename: Takashi
authors.initials: T
authors.lastname: Morita
authors.forename: Kimi
authors.initials: K
authors.lastname: Araki
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yamamura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tateishi
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005298:Fertility; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D006579:Heterozygote; D008297:Male; D051379:Mice; D009929:Organ Size; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012671:Seminiferous Tubules / Q000473:pathology; D013091:Spermatogenesis; D013093:Spermatogonia / Q000166:cytology / Q000378:metabolism; D013737:Testis / Q000166:cytology / Q000196:embryology* / Q000378:metabolism* / Q000637:transplantation
chemical_list: D015415:Biomarkers; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C485953:Rad18 protein, mouse