Mouse models for evaluating sex chromosome effects that cause sex differences in non-gonadal tissues

Abstract

XX and XY cells have a different number of X and Y genes. These differences in their genomes cause sex differences in the functions of cells, both in the gonads and in non-gonadal tissues. This review discusses mouse models that have shed light on these direct genetic effects of sex chromosomes that cause sex differences in physiology. Because many sex differences in tissues are caused by different effects of male and female gonadal hormones, it is important to attempt to discriminate between direct genetic and hormonal effects. Numerous mouse models exist in which the number of X or Y genes is manipulated, aiming to observe the effects on phenotype. In two models, namely the four core genotypes model and SF1 knockout gonadless mice, it is possible to detect sex chromosome effects that are not explained by group differences in gonadal hormones. Moreover, mouse models are available to determine whether the sex chromosome effects are caused by X or Y genes.

Figure 1

Robust sex chromosome effect on nociception. FCG mice were gonadectomised as adults and then tested for the development of tolerance to morphine. Mice were injected twice daily with morphine or saline, plus an NMDA antagonist or saline. On the seventh day, mice were tested on a hotplate at time zero and then injected with morphine and tested after 30, 60 and 90 minutes. The graph shows the latency for the mice to lick or shake their paws. All data are averaged across drug treatment groups. XX mice of either gonadal sex showed much lower latencies than XY mice (*, p<0.00001), and the presence of testes or ovaries prior to gonadectomy had no effect. From (30).

Figure 2

Chromosome maps of variants of the X and Y chromosomes. Progeny of XY* males, mated with XX females, are as follows: XX, XY*, XO, XY*^X, XX^Y*. Illustrated are the normal X and Y chromosomes, and the recombinant sex chromosomes Y*, Y*^X, and X^Y*. The pseudoautosomal region (PAR) is separated into proximal to distal segments A,B,C. XPB, X-PAR boundary. YPB, Y-PAR boundary. NPX, non-PAR region of the X chromosome. MSY, male-specific (non-PAR) region of the Y chromosome. From (39) and based on (68, 69).