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Specific arrest of spermatogenesis caused by apoptotic cell death in transgenic mice
1Furusawa MorphoGene Project, Research Development Corporation of Japan, ERATO, Tsukuba, Japan.
Background:
The c-myc protooncogene has been implicated in the control of cell proliferation, differentiation and/or apoptosis in various cellular systems. However, the role of c-myc in germ cell lineage is largely unknown.
Results:
We have produced transgenic mouse lines carrying the rat c-myc protooncogene under the control of human metallothionein promoter (hMT-c-myc). It was found that the male transgenic mice were sterile. In contrast, all of the female transgenic mice were completely fertile and transmitted the transgene to the next generation. However, male transgenic mice from the female transgenic founders were also found to be sterile. This sterility was due to a defect in spermatogenic cell differentiation, since virtually no sperm were seen within the seminiferous tubules or the cauda epididymis. Histological examination revealed that germ cell death occurred approximately 7 days after birth and, consequently, spermatogenesis was arrested at an early stage in meiotic division in the transgenic mice. Moreover, this germ cell death was found to be caused by apoptosis.
Conclusion:
We conclude that an excess level of c-myc expression in differentiating spermatogenic cells is responsible for the apoptotic death of germ cell, and that a decrease in c-myc level would be an obligatory step for the completion of normal spermatogenesis.
Insights
Overexpression of the c-myc protooncogene in male mice causes germ cell apoptosis and sterility. A decrease in c-myc levels is essential for normal spermatogenesis completion.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- The c-myc protooncogene regulates cell proliferation, differentiation, and apoptosis.
- Its specific role in the germ cell lineage remains largely uncharacterized.
Purpose of the Study:
- To investigate the function of c-myc in mammalian germ cell development.
- To determine the impact of c-myc overexpression on spermatogenesis.
Main Methods:
- Generation of transgenic mice expressing rat c-myc under a human metallothionein promoter (hMT-c-myc).
- Analysis of fertility, sperm production, and testicular histology in transgenic and wild-type mice.
- Assessment of germ cell apoptosis via histological examination.
Main Results:
- Male transgenic mice exhibited sterility due to defective spermatogenic cell differentiation.
- Germ cell death, caused by apoptosis, occurred around 7 days postpartum, arresting spermatogenesis.
- Female transgenic mice were fertile and transmitted the transgene, but their male offspring were sterile.
Conclusions:
- Excessive c-myc expression in differentiating spermatogenic cells induces apoptotic germ cell death.
- Downregulation of c-myc is a critical requirement for successful spermatogenesis.