What does the "four core genotypes" mouse model tell us about sex differences in the brain and other tissues?

Abstract

The "four core genotypes" (FCG) model comprises mice in which sex chromosome complement (XX vs. XY) is unrelated to the animal's gonadal sex. The four genotypes are XX gonadal males or females, and XY gonadal males or females. The model allows one to measure (1) the differences in phenotypes caused by sex chromosome complement (XX vs. XY), (2) the differential effects of ovarian and testicular secretions, and (3) the interactive effects of (1) and (2). Thus, the FCG model provides new information regarding the origins of sex differences in phenotype that has not been available from studies that manipulate gonadal hormone levels in normal XY males and XX females. Studies of the FCG model have uncovered XX vs. XY differences in behaviors (aggression, parenting, habit formation, nociception, social interactions), gene expression (septal vasopressin), and susceptibility to disease (neural tube closure and autoimmune disease) not mediated by gonadal hormones. Some sex chromosome effects are mediated by sex differences in dose of X genes or their parental imprint. Future studies will identify the genes involved and their mechanisms of action.

Fig. 1

FCG mice are produced by breeding XX gonadal females with XY^–Sry gonadal males, producing the four genotypes shown. The figure shows the genetic differences among the four genotypes, in presence/absence of the Y chromosome, number of X chromosomes, and genomic imprint on X genes. Below, FCG mice allow a 2 × 2 comparison to detect the phenotypic effects of sex (Sry present or absent) or sex chromosome (XX vs. XY).

Fig. 2

Sex chromosome effect on embryonic mesencephalic dopamine cells in vitro. Dissociated mesencephalic cells were harvested from embryonic day 14 mice, then grown in vitro for 11 days. The graph shows that the number of tyrosine hydroxylase (TH) neurons, as a ratio to number of MAP2-positive neurons, was higher in XY than XX FCG mice (**p < 0.000001). Sex had no significant effect. From [21]. Reprinted by permission from Macmillan Publishers Ltd.; from Nature Neuroscience 5:933, copyright 2002.

Fig. 3

Sex chromosome effect on response to nociceptive stimuli. FCG mice were injected daily for six days with morphine or saline, with or without an NMDA blocker. On the seventh day, mice were placed on a hotplate and tested for their response before (at 0 min) and after an injection of morphine. The graph shows the latency to lick the hindpaw, for each of the four genotypes. All drug treatment groups are combined in this graph to illustrate the overall main effect of sex chromosome complement. XX mice of both sexes showed considerably shorter latencies to respond (*p < 0.00001), before or after the injection of morphine after the zero time point. Latencies were increased after morphine injection more in the XY than XX groups (p < 0.05). From [43]. Reprinted from Hormones and Behavior [43], copyright 2008, with permission of Elsevier, Inc.

Fig. 4

Effect of sex chromosome complement on response of mice to active EAE (Experimental Autoimmune Encephalomyelitis). Gonadectomized FCG mice were induced to develop an immune response to an injected myelin autoantigen. The graph shows the clinical scores of males (A) and females (B) over time in days after injection of the autoantigen. Higher clinical score indicates more severed motor impairment: 0 indicates no impairment, 1 and 2 mild and moderate limb weakness, 3 hind limb paresis, 4 total hind limb paralysis, 5 pre-moribund. In each experiment, XX mice showed significantly more severe disease (p < 0.0001). From [76], copyright by the authors and published by the Rockefeller University Press.

Fig. 5

Effect of sex chromosome complement in a mouse model of Systemic Lupus Erythematosus (SLE). Mice were injected with pristane, and developed SLE-like symptoms including severe renal pathology. The graphs shows greater survival of XY than XX gonadectomized mice of each sex (females on left p < 0.04, males on right p < 0.03). From [76], copyright by the authors and published by the Rockefeller University Press.