VIth ICA - Symposium - Impact of Transgenic and Gene Knock-Out Studies on Understanding of Male Reproductive Functions (1996)

Of the three symposium lectures, one presented disruption of genes involved in testicular regulation, one overexpression on such genes and one tumorigenesis of the testis with targeted oncogene expression. These three presentations give good examples of the versatility of these novel techniques in exploration of various physiological and pathophysiological phenomena, in this case related to male reproduction.
In the first presentation, Raj Kumar (USA) showed fascinating data on knock-out studies of genes of inhibin-a, the activin b-subunits, activin receptor, anti-Müllerian hormone and follistatin and the effect on male reproductive physiology. Specific phenotypes of all models, too numerous to review in detail here, were found. In some cases the phenotypes were less dramatic than expected, which can be interpreted as a sign of redundancy in the biological regulatory systems. If one gene is inactivated, its functions are taken over by the others. One of the striking findings was the apparent tumor suppression function of inhibin; mixed sex cord stromal tumors developed in the gonads of the inhibin-a subunit deficient mice. In addition, these animals developed cachexia, which was due to liver effects of the concomitant high activin levels.

Another very interesting model was the recently developed FSHb subunit knock-out mouse. The role of FSH in regulation of male fertility has been a contentious topic, and the FSH-deficient mice gave an answer to a question what happens to male reproduction in the absence of FSH. The mice had somewhat reduced testicular size, suppressed spermatogenesis, but persistent fertility. In contrast, all female mice were infertile due to arrest of follicular maturation at the early antral stage. Hence, the revised concept about the role of FSH seems to be that it is needed for the determination of finite testis size through stimulation of prepubertal Sertoli cell proliferation, and for maintenance of quantitative normal spermatogenesis, but not for spermatogenesis per se or for fertility. Interestingly, these findings on the mouse are almost identical with a recently described phenotype of human males with inactivating FSH receptor mutation.

The topic of the presentation of Andrzej Bartke (USA) dealt with effects of over-expression of the growth hormone (GH) gene on male reproductive functions. GH overexpression can lead to significant alterations in plasma levels of gonadotropins and in the hypothalamic control of their release. However, testosterone secretion and most other testicular functions appears to be resistant to these changes. In contrast, the breeding performance of the animals seems to be suppressed, and many males are infertile. Behavioral defects were found as the reason for the defective reproductive performance; significant alterations were found in the copulatory behavior of many of the males. These mouse models provide a good example of the plasticity of the regulatory mechanisms of reproduction. Overexpression of a non-gonadotropic gene (GH) dramatically alters the central regulation of gonadotropin secretion and reproductive behavior. The testis appears to adapt to the former change, but the latter functions are permanently damaged by the altered GH expression.In the last presentation, G. Kondoh (Japan) reported on Leydig cell tumors that were induced in transgenic mice carrying a fusion gene construct containing the mouse mammary tumor virus long terminal repeat and human papilloma virus (HPV) 16 early promoters, and HPV16 E6 and E7 transforming genes as structural genes. Testicular Leydig cell tumors developed in the mice with high incidence at the age of 8-10 months. Upon characterization of the mechanism of tumorigenesis, it was found that the c-kit proto-oncogene tyrosine kinase was activated in an autocrine-paracrine manner. Expression of the kit ligand (steel factor) was found in the tumor, but not in normal Leydig cells. No role of altered p53 gene expression was found in the tumorigenesis. These types of transgenic tumor models will be of great importance in the future in exploring the genesis and regulation of malignant tumors. They will also be useful models for development of novel treatment strategies.

Ilpo Huhtaniemi, Finland