The Dysgenetic Gonad: Aberrant Testicular Differentiation

Abstract

It has been suggested that the heteromorphic X and Y sex chromosomes of the mammal arose from a homomorphic pair of homologous autosomes and that the X changed little during evolution, while the Y lost most of its genetic material to become a specialized testis-inducer (Ohno, 1967). Of course the sex determining role of the Y chromosome is borne out empirically: in the presence of the Y, the initially indifferent fetal gonad becomes a testis and in the absence of the Y, the gonad becomes an ovary. The newly organized testis secretes testosterone (to which both XV and XX cells can respond); this induces the secondary sex characteristics of the male and in the absence of testosterone, the embryo becomes a female (Jost, 1970; Wilson and MacDonald, 1978). Yet the scheme is rather more complicated, for presence of the V chromosome does not guarantee testicular differentiation and absence of the V does not guarantee ovarian differentiation; XV gonads may become ovaries and XX gonads may become testes and either may become ovotestes. Indeed there is a growing body of evidence that it is not the V chromosome itself that induces the testis, but a serologically defined, phylogenetically stable cell membrane component called ‘H-V antigen,’ synthesis of which is dependent either directly or indirectly on V chromosomal genes. In vitro, for example, XX cells of the dissociated neonatal ovary form seminiferous tubule-like aggregates in the presence of H-V antigen, whereas in the presence of H-V antibody, XV cells of the dissociated neonatal testis form ovarian ‘folliculoids.’ In vivo, H-V antigen is routinely detected in association with testicular differentiation, despite karyotype or secondary sex phenotype: XX males are H-V antigen positive (H Y+) and so are XV females with the testicular feminization syndrome; remarkably, XX true hermaphrodites (possessing both testis and ovary) manifest H-V phenotypes intermediate between those of normal male and female (reviewed in Ohno, 1979). Thus cell surface immunogenetics has provided a valuable new testing ground for the study of sex determination and reproductive biology. In this paper I shall review some of the advances of the past few years, emphasizing studies of abnormal differentiation in the human gonad. I intend to show that ovarian organogenesis of the XV gonad and testicular or ovotesticular differentiation of the XX gonad, may each be attributed to errors of synthesis, dissemination and binding of serologically detectable H-V antigen.