Evidence that the testis determination pathway interacts with a non-dosagecompensated, X-linked gene

In a number of mammals, including mouse and man, it has been shown that at equivalent gestational ages, males are developmentally more advanced than f emales, even before the gonads form. In mice, although some strains of Y ch romosome exert a minor accelerating effect in pre-implantation development, it is a post-implantation effect of the difference in X chromosome constit ution that is the major cause of the male/female developmental difference. Thus XX females are retarded in their development by about 1.5 h relative t o (XO)-O-M females or XY males; however, they are more advanced than (XO)-O -P females by about 4 h. It has been suggested that this early developmenta l difference between XX and XY embryos may "weight the dice" in favour of o varian and testicular development, respectively, although expression of Sry will normally overcome any such bias. Here we test this proposal by compar ing the relative frequencies of female, hermaphrodite and male development in (XO)-O-P, XX and (XO)-O-M mice that carry an incompletely penetrant Sry transgene. The results show that testicular tissue develops more frequently in XX,Sry transgenics than in either of the two types of XO transgenics. T hus the incidence of testicular development is affected by X dosage rath er than by the developmental hierarchy. Th is implies there is a non-dosage c ompensated gene (or genes) on the X chromosome, which interacts with the te stis-determining pathway. Since the pseudoautosomal region (PAR) is known t o escape X-inactivation, penetrance of the Sry transgene was also assessed in (XY)-Y-M*(X) mice that have two doses of the PAR but have a single dose of all genes proximal to the distal X marker Amel. These mice showed simila r levels of testicular development to (XO)-O-M mice with the transgene; thu s the non-dosage compensated X gene maps outside the PAR.