Testis-organizing H-Y antigen and the primary sex-determining mechanism of mammals

Embryonic indifferent gonads of mammals have the inherent tendency to develop toward the ovary. The precise meaning of this general statement is likely to be the bisexual expression of the ovary-organizing plasma membrane component and its specific membrane-bound receptor. Testicular organogenesis that normally, but not always, depends upon the presence of the Y-chromosome is the responsibility of the two plasma membrane components; the male-specific but ubiquitously expressed H-Y antigen and its specific receptors expressed only by gonadal cells, but of both sexes. Of these four components for mammalian gonadal organogenesis, only the expression of H-Y antigen is confined to the heterogametic male sex. Accordingly, this plasma membrane component, which has been conserved in evolution to the extreme, emerges as the master regulator of the primary (gonadal) sex-determining mechanism of mammals. Its ubiquitous as well as constitutive expression in the male reflects its master regulatory role, since a master by definition is not under genetic subjugation. Testis-organizing H-Y antigen is not an integral component of the plasma membrane. Instaed, it utilizes β2-microglobulin-MHC (H-2 of the mouse and HLA of man) antigen dimers as its plasma membrane anchorage sites. This enables H-Y antigen to play a hormonelike role during testicular organogenesis. By so doing, H-Y antigen drives out the bisexually expressed, rival ovary-organizing antigen from the plasma membrane and virtually monopolizes the β2m-MHC antigen dimer anchorage sites of male gonadal cells. In the mouse, this monopolization by H-Y renders much of H-2 antigenic determinants inaccessible to anti-H-2 antibody. Hence, fetal and newborn testicular cells are totally resistant to the cytotoxic effect of anti-H-2 antibody.