1022-7954/02/3802- $27.00 © 2002 MAIK “Nauka /Interperiodica” 0138 Russian Journal of Genetics, Vol. 38, No. 2, 2002, pp. 138–147. Translated from Genetika, Vol. 38, No. 2, 2002, pp. 196–206. Original Russian Text Copyright © 2002 by Ahmerova, Svechnikov, Osadchuk. INTRODUCTION Leydig cells are the main steroidogenesis sites for andronens including testosterone, the major sex hor- mone of males of most mammalian species. Testoster- one plays the key role in ontogenetic formation and the maintenance of the male phenotype. Though ontoge- netic mechanisms of the reproductive system hormone function formation have been thoroughly studied, the genetic control of these mechanisms still remains in question. A collection of genetically homogenous inbred mouse strains can be utilized for the resolution of this problem. In recent years the studies of the origin, growth, and functional regulation of Leydig cells during pre- and postnatal development have achieved considerable progress. Regulation of steroidogenesis in Leydig cells is a complex process, which involves all levels of the hypothalamic-pituitary-gonadal system. Furthermore, at different ontogeny stages, in the course of the complex “life cycle” of Leydig cells, the role of a certain regula- tion level is being changed [1–6]. It was established that expression of the genes encoding the key enzymes of steroidogenesis is characterized by multilevel regula- tion. This regulation involves luteinizing hormone (LH), cAMP, androgens, growth factors, and cytokinins as well as transcriptional factors (“orphan” nuclear receptors: SF-1, DAX-1, Sox-9, COUP-TP, and NGFI-B) [7–9]. It is apparent that mutations in the genes encod- ing the key enzymes of steroidogenesis and their regu- latory proteins can result in serious abnormalities of reproductive function, sterility, and even in the loss of viability. For instance, in mice the knockout of the SF-1-encoding gene involves the whole gonadal-pitu- itary hypothalamic axis leading to complete degenera- tion not only of the testes, but also of the adrenals; the gonads develop according to the female type. Since SF-1 is an important regulator of steroid hydroxylases, which affects differentiation of the gonads and adrenals, these animals die within 8 days after birth from acute adrenocortical insufficiency [10]. These mutations dramatically disturb the reproductive func- tion and are rapidly eliminated by natural selection. In contrast to this type of genetic variability, our genetic model is based on genes with relatively mild and fine action, which do not block reproduction, and hence, are widely distributed in natural populations. This model is based on hereditary variability of the Leydig cell hormone function in the mice from six inbred strains contrasting in reproductive success, social dominance, and plasma testosterone levels [11–15]. Our genetic model can serve as an effective tool for analyzing genetic control of the Leydig cell hormone activity formation during postnatal ontogeny. The genetic control of the testis hormone function formation during postnatal development has been so far poorly investigated [16–19]. In our earlier studies of adult male mice from six inbred strains, correlated interstrain genetic variability in cAMP- and substrate- The Role of Genotype in the Formation of Leydig Cell Hormone Function during Postnatal Ontogeny in Diallele Crosses of Laboratory Mice L. G. Ahmerova, K. V. Svechnikov, and A. V. Osadchuk Institute of Cytology and Genetics, Russian Academy of Sciences, Novosibirsk, 630090 Russia; fax: (3832)33-12-78; e-mail: osadchuk@bionet.nsc.ru Received April 16, 2001; in final form, July 12, 2001 Abstract—Production of testosterone by Leydig cells in the postnatal ontogeny during sexual maturation under in vitro stimulation by chorionic gonadotropin, dibutiryl-cAMP, and pregnenolon was studied in males of four inbred mouse lines (BALB/c, PT, CBA/Lac, and A/He) and their F1 reciprocal hybrids. Highly statistically sig- nificant association between the animal genotype and age was revealed for all parameters studied, which indi- cates the genotype-dependent formation of the Leydig cell hormone function during the postnatal ontogeny. The effect of genotype was characterized by two specific features. First, in each postnatal ontogeny stage exam- ined correlative genetic variability of the cAMP- and substrate-dependent Leydig cell responsiveness was observed. Second, during postnatal ontogeny coordinated genetic variability underwent substantial ontogenetic changes. Definite pattern of genetic differences in the Leydig cell hormone activity was formed only at the late pubertal–early post-pubertal stage (60th day after birth). This process coincided with the completion of the Ley- dig cell morphological differentiation and the appearance of mature cells in the population. Thus, formation of the Leydig cell hormone function during postnatal ontogeny is under coordinated genetic control, which itself undergoes significant changes during sexual maturation. GENERAL GENETICS