A Model System for Study of Sex Chromosome Effects on Sexually Dimorphic Neural and Behavioral Traits

Abstract

We tested the hypothesis that genes encoded on the sex chromosomes play a direct role in sexual differentiation of brain and behavior. We used mice in which the testis-determining gene (Sry) was moved from the Y chromosome to an autosome (by deletion of Sry from the Y and subsequent insertion of an Sry transgene onto an autosome), so that the determination of testis development occurred independently of the complement of X or Y chromosomes. We compared XX and XY mice with ovaries (females) and XX and XY mice with testes (males). These comparisons allowed us to assess the effect of sex chromosome complement (XX vs XY) independent of gonadal status (testes vs ovaries) on sexually dimorphic neural and behavioral phenotypes. The phenotypes included measures of male copulatory behavior, social exploration behavior, and sexually dimorphic neuroanatomical structures in the septum, hypothalamus, and lumbar spinal cord. Most of the sexually dimorphic phenotypes correlated with the presence of ovaries or testes and therefore reflect the hormonal output of the gonads. We found, however, that both male and female mice with XY sex chromosomes were more masculine than XX mice in the density of vasopressin-immunoreactive fibers in the lateral septum. Moreover, two male groups differing only in the form of their Sry gene showed differences in behavior. The results show that sex chromosome genes contribute directly to the development of a sex difference in the brain.

Sex chromosome complement affects social interactions in mice

“…Olfaction is particularly important for social interactions and our finding of no differences in latency to find a food item, most mice finding the buried food in less than 20 s, confirms pervious data which require more complex olfactory function. Olfactory preference for male-versus femalesoiled bedding, social recognition (Gatewood et al, 2006) and time spent sniffing an anaesthetized male or female mouse (De Vries et al, 2002) have been investigated using the FCG. In the preference studies we noted the previously described gonadal sex effects; males spend more time sniffing females and their odors than do females.…”

“…Development and production of the four core genotype (FCG) mouse model has been described previously (De Vries et al, 2002;Gatewood et al, 2006). Briefly, the cross uses males carrying a 129/SvEv-Gpi1 c Y chromosome (Simpson et al, 1997) with an 11 kb deletion removing the testis-determining gene Sry (Gubbay et al, 1992).…”

“…The neural bases of these behaviors are, in part, sculpted by the actions of gonadal steroids and genes downstream of the steroid receptors during development (MacLusky and Naftolin, 1981;Morris et al, 2004). This concept has been a major force behind decades of important research, yet, the discovery of "exceptions" to this rule has stimulated alternative hypotheses including the examination of sex chromosome complement as a source for neural and behavioral differences between males and females (Carruth et al, 2002;De Vries et al, 2002).…”

“…To manipulate sex chromosome complement independently of gonadal steroid exposure we use a mouse model that incorporates a spontaneous mutation of the Sry gene on the Y sex chromosome (referred to as Y − ) and a Sry transgene that randomly inserts on an autosome, thus, testes determination is disassociated from sex chromosome complement (De Vries et al, 2002). As a result, all individuals possessing the Sry transgene develop testes and have a male external phenotype, regardless of their sex chromosome complement while individuals lacking the transgene have external female secondary sex characteristic and ovaries.…”

“…Perinatal T levels have not been directly measured in the FCG. However, two sexually dimorphic measures that reflect perinatal T; numbers of tyrosine hydroxylase containing cells in the anterior paraventricular nucleus (AVPV) and anogenital distances (De Vries et al, 2002;Rissman, unpublished data) are not affected by sex chromosome complement.…”