Heritable Imprinting Defect Caused by Epigenetic Abnormalities in Mouse Spermatogonial Stem Cells

• Published in: Biology of reproduction 2009-03, Vol.80 (3), p.518-527
• Main Authors: Lee, Jiyoung, Kanatsu-Shinohara, Mito, Ogonuki, Narumi, Miki, Hiromi, Inoue, Kimiko, Morimoto, Takeshi, Morimoto, Hiroko, Ogura, Atsuo, Shinohara, Takashi
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Body Weight - genetics; Body Weight - physiology; Cells, Cultured; DNA Methylation; Embryology: invertebrates and vertebrates. Teratology; Embryonic Stem Cells - cytology; Embryonic Stem Cells - physiology; Epigenesis, Genetic - physiology; Fundamental and applied biological sciences. Psychology; Genomic Imprinting - physiology; Germ Cells - cytology; Germ Cells - physiology; Histones - genetics; Histones - metabolism; Male; Mice; Mice, Inbred ICR; Molecular embryology; Spermatogenesis - physiology
• ISSN: 0006-3363; 1529-7268
• DOI: 10.1095/biolreprod.108.072330

Male germ cells undergo dynamic epigenetic reprogramming during fetal development, eventually establishing spermatogonial stem cells (SSCs) that can convert into pluripotent stem cells. However, little is known about the developmental potential of fetal germ cells and how they mature into SSCs. We developed a culture system for fetal germ cells that proliferate for long periods of time. Male germ cells from embryos 12.5-18.5 days postcoitum could expand by glial cell line-derived neurotrophic factor, a self-renewal factor for SSCs. These cells did not form teratomas, but repopulated seminiferous tubules and produced spermatogenesis, exhibiting spermatogonia potential. However, the offspring from cultured cells showed growth abnormalities and were defective in genomic imprinting. The imprinting defect persisted in both the male and female germlines for at least four generations. Moreover, germ cells in the offspring showed abnormal histone modifications and DNA methylation patterns. These results indicate that fetal germ cells have a limited ability to become pluripotent cells and lose the ability to undergo epigenetic reprogramming by in vitro culture.