HST-1/FGF-4 gene activation induces spermatogenesis and prevents adriamycin-induced testicular toxicity

• Published in: Oncogene Vol. 21; no. 6; pp. 899 - 908
• Main Authors: YAMAMOTO, Hanako, OCHIYA, Takahiro, KAKIZOE, Tadao, TERADA, Masaaki, TAMAMUSHI, Shoujiro, TORIYAMA-BABA, Hiroyasu, TAKAHAMA, Yasushi, HIRAI, Kotaro, SASAKI, Hideo, SAKAMOTO, Hiromi, SAITO, Izumu, IWAMOTO, Teruaki
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 31.01.2002; Nature Publishing Group
• Subjects: Adenoviridae - genetics; Adenoviruses; Age Factors; Ageing, cell death; Aneuploidy; Animals; Antineoplastic Agents - toxicity; Antitumor agents; Biological and medical sciences; Biotechnology; Cell physiology; Cre recombinase; DNA - analysis; Doxorubicin - toxicity; Fertility; Fibroblast Growth Factor 4; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - physiology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Gene therapy; Genetic Vectors - genetics; Health. Pharmaceutical industry; Humans; Industrial applications and implications. Economical aspects; Integrases - genetics; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular and cellular biology; Organ Size - drug effects; Ploidy; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - physiology; Recombinant Fusion Proteins - physiology; RNA, Messenger - biosynthesis; Sertoli Cells - metabolism; Sperm Count; Spermatogenesis; Spermatogenesis - drug effects; Spermatogenesis - genetics; Testes; Testis - drug effects; Testis - pathology; Toxicity; Transcriptional Activation; Transgenic mice; Viral Proteins - genetics; Virus; Signal transduction; Phosphorylation; Adenoviridae; Enzyme; Induction; Mitogen-activated protein kinase; Activation; Gene therapy; Vector; Apoptosis; Genetic transfer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1205135

We previously demonstrated expression of the HST-1/FGF-4 gene in the testis of normal adult animals, which suggests its possible role in spermatogenesis. For an understanding of its functional significance in the testis, conditional transgene expression was used. Precise genetic switches can be efficiently generated in a straightforward manner using adenovirus-carrying Cre recombinase, which means our new strategies promise to contribute substantially to a better and prompt understanding of the functions of genes in vivo by controlling the expression of any gene to any organ at any desired time. Our new method demonstrated for the first time that the specific gain of function of the HST-1/FGF-4 gene in the testis resulted in markedly enhanced spermatogenesis. To further investigate the function and therapeutic potency of HST-1/FGF-4, transgenic mice with enhanced HST-1/FGF-4 expression in the testis were exposed to adriamycin (ADR), an anticancer drug causing severe testicular toxicity. Degree of damage to spermatogenesis was assessed by sperm count, testicular weight, histology, and DNA ploidy. Induced expression of HST-1/FGF-4 markedly enhanced the recovery of ADR-induced testicular damage. Furthermore, adenoviruses carrying the HST-1/FGF-4 gene ameliorated testicular toxicity of ADR. These results with new adenovirus-mediated Cre/lox conditional mice indicated that HST-1/FGF-4 could be an important factor for spermatogenesis, presenting a new paradigm to treat impaired fertility.