HY antigen: Genetic control and role in testicular differentiation

Anatomic and functional development of male sexual apparatus is a complex process initiated at conception. Genetic instruction encoded on sexual and autosomal chromosomes programs the differentiation of gonadal anlagen into a functioning testis. This, in turn, induces the transformation of primitive bisexual genital structure toward male phenotype. Due to recent advances in molecular genetics and immunology, the answer to the basic question of why a male becomes a male is just beginning to unravel. This report discusses in perspective various hypotheses concerning the influence of genetic inheritance on gonadal differentiation of male. Discovery of a sex-related difference in the distribution of the chromatin in cat’s neurons was the first indication that the genetic makeup is the motor behind somatic sexual development.’ This concept was strengthened when Tijo and LevarP then Ford and Hamerton3 established the karyotype in 1956. Identification of XY as the male sex chromosomes led to the question as to whether or not both X and Y or. only one of the chromosomes carries the genetic key to male sexual differentiation. One of the early indications that the Y chromosome is intimately involved in determination of male sexual characters derived from the genetic studies of Welshons and Russell and Russell and Chu.4 They discovered that in mice, fertile females have XX or X0 chromosome patterns, whereas the males always have a Y chromosome besides one or more X. Since, regardless of the number of X chromosomes, the Y is constantly part of the sex chromosome pattern in males, it was assumed that the Y chromosome is the carrier of a male-determining factor which induces the transformation of the primordial gonadal anlagen into a functioning masculine gonad. This concept was supported by discovery of such human patterns as 47 XXY, 48 XXXY, 47 XYY, and 49 XYYYY in apparently normal males5 No active role for the X chromosome in male sexual differentiation was foreseen at that time. How would genetic information encoded on the Y chromosome translate into male-determining factor? Our present knowledge regarding biochemical base of genetic sexual differentiation originates from Eichwald and Silmser’P experiments of organ transplantation. Eichwald and Silmsere and later Sachs and HelIe? studied the immunologic response of highly inbred strains of mice transplanted with skin from one to the other. These highly inbred strains of mice behave biologically as identical twins and theoretically should show no signs of transplant incompatibility. Indeed, the skin graft survived when transplanted from male to male, female to female, and female to male, but it was rejected when the donor was a male and the recipient was a female. Since the only difference between donor and recipient was the Y ‘%hromosome, the researchers assumed that the Y is responsible for a surface antigen which induced the rejection of skin, the antigen being either the male-determining factor of another substance involved specifically in male sexual differentiation. This surface antigen was named the histocompatibility Y or the HY antigen by Billingham and Silvers8 One significant step forward in our understanding of male sexual differentiation was made by Goldberg and his colleagues in 1971.Q They showed that sera from female mice grafted with male skin are cytotoxic for sperm in the presence of complement. The cytotoxic