ReviewWhat does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues?
Section snippets
1. Introduction
The vast majority of natural phenomena cannot be explained by experimental studies of those phenomena themselves, because the number of phenomena greatly exceeds the number of scientists. Instead, scientists study a restricted set of phenomena, from which they extract principles that are generalized to explain other phenomena. The model systems, if chosen appropriately, can yield generally useful rules that are found to govern the function of other systems. Individual model systems often
2. How FCG mice were made
FCG mice involve two critical genetic components: the deletion of the testis-determining gene Sry from the Y chromosome, first reported by Lovell-Badge and Robertson [55], and the insertion of an Sry transgene onto an autosome in the same mice, achieved by Burgoyne and colleagues [56]. The Y chromosome of these mice sustained a spontaneous deletion that removed the entire Sry gene, yielding the “Y minus” chromosome (Y−) that not longer is testis-determining. XY− mice thus are gonadal females (
3. Genetic differences in XX vs. XY FCG mice
When same-sex XX and XY mice differ in the FCG model, we conclude that the difference is caused by a “sex chromosome effect”. There are numerous possible genetic origins for such effects (Fig. 1). (1) Y gene dose: XY mice are influenced by Y genes, but XX mice are not. (2) X gene dose: XX mice experience a higher expressed dose of X genes by virtue of the double genomic dose of X genes, in contrast to the single dose in XY mice. Although most dosage-related sex differences in X gene expression
4. The first use of FCG mice in studies of the brain and behavior
When FCG mice were first used to study sex differences in brain and behavior, the goal was to investigate well-known sexually dimorphic phenotypes that had previously shaped the literature [37], [57], [80]. Mice were gonadectomized as adults and then treated with equal levels of testosterone. The first question was whether sex chromosome complement played any role in sexual differentiation. For most phenotypes studied, the answer was “no”. The phenotypes selected for analysis had all been
5. More sex chromosome effects
In recent years FCG mice have been utilized to test for sex differences in diverse phenotypes, and large sex chromosome effects have been found in neural and non-neural systems.
6. Experimental designs and interpretation
The FCG mouse model has been applied so far mostly as a test of the hypothesis that some sex differences in phenotype result from the action of sex chromosome complement (XX vs. XY). In part, these experiments are a reaction to previous theories that attributed all sex differences to the effects of gonadal hormones. Because of this emphasis, we and other investigators have usually sought to reduce effects of gonadal hormones as much as possible, so that sex chromosome effects could be detected.
7. Changes in the dogma required by outcomes of studies of FCG mice
The study of sex differences has been changed by the realization that XX and XY cells are not equivalent. The change has been slow to develop, and is ongoing.
8. Future prospects
Three major developments will improve our understanding of direct sex chromosome effects on sex differences in phenotypes. First, as the number of studies increases, we will be better able to judge how widespread sex chromosome effects are, and how important they are. To date, only a limited number of neural and behavioral phenotypes have been tested. Second, currently we almost completely lack information about how sex chromosome complement interacts with the effects of hormones, for example
Acknowledgments
The development and testing of the FCG mice has been the result of a large collaborative effort across numerous labs. Paul Burgoyne and colleagues had the insight to combine the Y− chromosome with the Sry autosomal transgene, which led to a breakthrough in the study of sexually dimorphic phenotypes. We are indebted to the following people for many critical discussions of the ideas and results discussed here: Paul Burgoyne, Robin Lovell-Badge, Emilie Rissman, Geert De Vries, Amanda Swain,
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