The elusive action of sex-determining genes: mitochondria to the rescue?

According to the accepted dogma of mammalian sex determination, the Y-linked gene SRY initiates male development by inducing hitherto uncommitted somatic cells of the fetal gonad to develop into Sertoli cells. However, it has become evident that the correct functioning of an increasing number of genes on other chromosomes is required for testicular organogenesis. They include the SRY-related gene, SOX9, which plays important roles in both sex determination and chondrogenesis, as well as genes responsible for the production of growth factors, i.e. fibroblast growth factor 9, platelet derived growth factor A, and the members of the insulin-receptor family of genes. It is known, moreover, that differences between the sexes begin to develop long before the differentiation of Sertoli cells, including an increase in gonadal size and cell proliferation, and accelerated development of XY embryos at early pre-implantation stages. There is also evidence of transcription of Y-linked, and of X-linked, genes and of an enhanced metabolic rate in XY embryos. Furthermore, the condition of true hermaphroditism does not fit into a simple genotype/phenotype relationship. The proposal that "testis-determining" genes act by increasing metabolic rates rather than directly determining Sertoli cell differentiation can account for a number of observations that do not fit the current model, including pregonadal sex differences, the activity of the same gene in different organ systems, and the frequent co-existence of sexual and somatic abnormalities. It also sheds light on the pervasive differences between metabolic rates of mammalian males and females, while the facts of true hermaphroditism can be viewed as remnants of temperature-dependent sex determination in ectothermic vertebrates. Growing interest in mitochondria, which play a central role in the provision of energy to eukaryotic cells, makes a shift of paradigm from gonadal histology to energy metabolism timely, particularly since new techniques have become available for testing the hypothesis, and for widening the experimental approach to sex determination. If the hypothesis is correct, it would mean that male sex is determined by nuclear genes inherited from the father regulating the activity of maternally derived mitochondria.