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0013-7227/04/$15.00/0 Printed in U.S.A. Endocrinology 145(3):1057–1062 Copyright © 2004 by The Endocrine Society doi: 10.1210/en.2003-1491 Minireview: Sex Chromosomes and Brain Sexual Differentiation ARTHUR P. ARNOLD, JUN XU, WILLIAM GRISHAM, XUQI CHEN, YONG-HWAN KIM, YUICHIRO ITOH AND Department of Physiological Science and Laboratory of Neuroendocrinology of the Brain Research Institute, University of California, Los Angeles, Los Angeles, California 90095 The brains of males and females differ, not only in regions specialized for reproduction, but also in other regions (controlling cognition, for example) where sex differences are not necessarily expected. Moreover, males and females are differentially susceptible to neurological and psychiatric disease. What are the origins of these sex differences? Two major sources of sexually dimorphic information could lead to sex differences in brain function. Male and female brain cells carry a different complement of sex chromosome genes and are influenced throughout life by a different mix of gonadal hormones. Until recently all sex differences in the brain have been attributed to the differential action of gonadal hor- T HE CLASSIC DOGMA of sexual differentiation in mammals and birds states that the genetic sex of the animal determines the animal’s gonad type, and that the phenotype of nongonadal tissues is thereafter controlled by the gonadal secretions (1). In mammals, the Y-linked Sry gene is expressed in sexually undifferentiated cells of the primitive genital ridge and commits that tissue to a testicular fate (2). The testes then secrete hormones: Müllerian-inhibiting hormone, which prevents development of Müllerian ducts (3); and testosterone, which promotes development of masculine structures elsewhere in the body, including those in the brain. Because some central nervous system regions and behaviors can be fully sex-reversed by treating females with testosterone, or preventing the action of testicular hormones in males (e.g. Ref. 4), no other factor need be invoked to explain the sexual differentiation process in those cases. In other cases, sex differences precede the onset of gonadal secretions, or appear not to be explained by gonadal secretions, suggesting that they may be caused by other sexually dimorphic signals. Original Evidence for Sex Chromosome Effects on Sexual Differentiation of Nongonadal Tissues It is difficult to identify the first evidence that sex differences in mammalian or avian traits are caused by the differential representation of sex chromosome genes in the genomes of males and females. X-linkage of some sex-biased traits such as color blindness has been understood for about 100 yr (5) but seems not to have been considered relevant to Endocrinology is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community. mones. Recent findings, however, suggest that brain cells that differ in their genetic sex are not equivalent, and that difference may contribute to sex differences in brain function. Here we discuss evidence for sex chromosome effects on both neural and nonneural systems, which together provide support for the idea that XX and XY cells differentiate even before they are influenced by gonadal hormones, and even if they are exposed to similar levels of gonadal steroids. Fortunately, new model systems for studying sex chromosome effects have recently been developed, and they should help in testing further the role of sex chromosome genes. (Endocrinology 145: 1057–1062, 2004) theories of sexual differentiation at least since the 1940s when Jost demonstrated the endocrine control of differentiation of external genitalia and other structures (6). Other evidence from the 1920s and 1930s suggested that some secondary sexual characteristics are not hormonally determined. Sexual plumage typical of the male and female birds can occur in the same individual, for example in lateral gynandromorphic birds, as was realized by the 1920s (7). By modern standards, these early studies usually stopped short of proving a sex chromosome effect on sexual characters because of the difficulty in establishing the chromosomal sex of cells. Even today, genetic sex is normally confounded with the type of hormonal secretions of the gonads, making it difficult to exclude an endocrine mechanism rigorously. More recently, several studies have indicated that sex differences are found in tissues before gonadal differentiation. Male and female embryos from several species differ in size at specific gonadal stages (8, 9), a difference influenced by both X and Y genes in mice (10 –12). In the mouse, the genetic origin of the sex difference is understood better than for most other cases, but it is not clear to what extent the early developmental differences influence adult phenotypes. In the marsupial wallaby, differentiation of the scrotum, pouch, and mammary tissues appears to be under control of the number of X chromosomes (one X causes differentiation of male structures, two cause feminine differentiation), based on observations of animals with unusual numbers of sex chromosomes (13–15). The scrotum and mammary tissues are recognizable before gonadal sex is evident. The wallaby example is the clearest case of functionally important sexspecific reproductive tissues that differentiate sexually because of the complement of sex chromosome genes in mammals. In the brain, Reisert and colleagues (16, 17) found that 1057 1058 Endocrinology, March 2004, 145(3):1057–1062 XX and XY cells, harvested from the midbrain of embryonic rats before the onset of sexually dimorphic plasma levels of testosterone, develop different phenotypes when grown in culture under identical conditions. Midbrain cultures develop different numbers of dopamine neurons, for example, and other differences in dopamine-related phenotypes (18). In this case, the sex differences are unlikely to have been caused by differences in gonadal secretions, and therefore probably result from the differential expression of sex chromosome genes in the cells. Sex differences in gene expression are also found in the mouse brain before gonadal differentiation (19). Sexual Differentiation of the Zebra Finch Song System The neural circuit for song in zebra finches (Taeniopygia guttata) illustrates some of the difficulties in separating the effects of gonadal hormones and sex chromosome genes, especially in a species not yet amenable to genetic modification (20). Male zebra finches sing a courtship song that females cannot sing, and the neural song circuit is much larger in males (more neurons, larger volumes of song regions, etc.) (21). Females treated at hatching with estradiol have a song circuit that is masculinized permanently and they sing as adults (22). This finding suggested that the male’s testes secrete testosterone during early stages of development, which is converted locally in the brain to estradiol, which acts via estrogen receptors to cause masculine development in a manner similar to sexual differentiation of various brain phenotypes in rodents (23, 24). The masculinizing role for estrogen is also supported by several experiments in which fadrozole, an aromatase (estrogen synthase) inhibitor, was found to reduce or block specific components of the normal masculinization of males, including the malespecific increase in androgen receptors (25–27). However, other experimental findings question the primacy of gonadal hormones and suggest a role for other factors. The dose of estradiol needed for substantial masculinization of females is rather high, and sex differences in plasma levels of steroids have been difficult to find. Treating females with various combinations of androgens and estrogens causes at best about half-masculinization of their song circuit, and they are never fully sex-reversed (28 –30). Moreover, blocking steroid action in males does not usually substantially prevent masculine development (31). The main experimental tool available has been to manipulate the levels of gonadal hormones, which tells us mainly about the role of hormones, not the role of other factors. When these manipulations are not effective, the results do not strongly undermine a hormonal theory because technical issues (e.g. wrong dose or time of treatment) could be invoked to explain the lack of effect in each case. In the aggregate, however, hormonal theories have not been adequate to predict the outcomes of experiments. One interesting approach has been to sex-reverse the gonads of genetic females, causing differentiation of testicular tissue in genetic females, to test the importance of testicular vs. ovarian secretions in brain sexual differentiation (32). In birds, ovarian differentiation requires estrogen and is inhibited at early embryonic stages when the embryo is treated Arnold et al. • Minireview with an inhibitor of estrogen synthesis. These genetic females have a right testis that makes sperm and a left ovotestis. Although these testes are large, secrete androgens, and partially masculinize the syrinx (vocal organ), the brains of these genetic females are masculinized little or not at all (32–34). This result indicates that large amounts of testicular tissue are not sufficient to masculinize the brain in genetic females and suggests that some other factors need to be invoked. The main caveat in interpreting these results is that the testes of these animals may not have secreted normal levels of gonadal steroids at all stages of life. Nevertheless, if the testes are the primary source of a masculinizing hormone, it is fair to expect significant masculinization of the brain of the testesbearing females, which was not observed. The ideal experiment to test the role of sex chromosome genes in sexual differentiation would be to expose genetically male and female brain cells to an equivalent level of gonadal hormones and test for differences in sexual phenotype. The discovery of a rare lateral gynandromorphic zebra finch allowed such a test (35). This animal had male plumage and a testis on the right side of its body, and female plumage and an ovary on the left (Fig. 1). Tests of genomic DNA indicated that the W chromosome, found normally only in females (which are ZW in contrast to ZZ males), was present at a higher level on the left side of the animal. In the brain, W-linked genes were expressed much higher on the left side than on the right, and Z-linked genes were expressed higher on the right (Fig. 1), as would be expected if the left brain were ZW and right brain ZZ. In two brain regions, the phenotype of the song circuit was more masculine on the genetically male side of the brain than on the female side (Fig. 1). Because the two sides of the brain differed in the complement of sex chromosomes but not in their exposure to gonadal hormones, the lateral difference in masculinity can be attributed to the lateral difference in genetic sex of the brain cells themselves. Because the genetically female side of the brain was more masculine than that of a normal female, however, it appears that hormonal (endocrine or paracrine) factors from the male side may have diffused to the genetically female side, causing partial masculinization. Evidence suggests that the brain itself may be responsible for de novo estrogen synthesis that is higher in males (36). Thus, one scenario is that the genetically male brain tissue secreted estrogen that caused incomplete masculinization of the female side. A Rodent Model for Assessing the Role of Sex Chromosome Genes Recent advances in the field of sex determination have yielded important new mouse model systems for studying the role of sex chromosome genes in sexual differentiation. By interfering with the genes responsible for gonadal differentiation, it is possible to produce an XY mouse with ovaries or an XX mouse with testes. Thus, mice with different complements of sex chromosomes (XX vs. XY) but with the same gonadal type can be compared to determine whether the sex chromosomes influence specific traits. In one model, the Y chromosome is deleted for the testis-determining gene Sry, producing the Y⫺ (Y minus) chromosome (37). XY⫺ mice Arnold et al. • Minireview FIG. 1. A lateral gynandromorphic zebra finch (top left and middle panels) had a male plumage (orange cheek patch, chest bar, and stripes) on the right (R) side and female plumage on the left (L), divided sharply at the midline (35). Right top shows autoradiograms of in situ expression of androgen receptor mRNA, a marker for song nucleus HVC, at several levels in frontal sections through the telencephalon, illustrating the more masculine nucleus on the genetically male side of the brain. Bottom panels show frontal brain sections with in situ expression of W-linked female-specific ASW mRNA (left; dark is area of expression) limited largely to the left half of the brain, and the Z-linked PKCIZ mRNA that was higher on the right side. The expression pattern is compatible with a ZW genotype on the left and ZZ genotype on the right. Reprinted from Proceedings of the National Academy of Sciences (35). have ovaries and on that basis are called females here (mice with testes are defined as males). In other mice, an Sry transgene is added back onto an autosome, reconstituting the male as XY⫺Sry (38). Breeding XY⫺Sry males to XX females produces four types of offspring: XX females, XY⫺ females, XXSry males, and XY⫺Sry males. XX and XY⫺ mice both have Endocrinology, March 2004, 145(3):1057–1062 1059 ovaries but differ in the genetic sex of their cells, so that differences between these females can be attributed to the complement of sex chromosomes. Similarly, comparing XXSry and XY⫺Sry mice tests for differences caused by the complement of sex chromosomes acting in a masculine hormonal environment. Numerous sexual phenotypes have been measured in the brain and behavior of these mice, including male reproductive behavior, social investigation behavior, and the morphology of various sexually dimorphic central nervous system regions including the cerebral cortex, hypothalamus, septum, and spinal cord (39, 40). All measurements were made in gonadectomized adults treated with equal levels of testosterone, or in gonadally intact newborn mice (41). For most of these variables, mice with testes (XXSry and XY⫺Sry) are more masculine than mice with ovaries (XX and XY⫺), and the sex chromosomes induce no group differences in mice with same gonadal type (Fig. 2). For example, female mice have more dopamine neurons in the anteroventral periventricular nucleus of the preoptic region, which controls ovulation, than male mice, irrespective of genetic sex of their cells. These findings indicate that gonadal hormones are responsible for induction of these sex differences, and no role for the sex chromosomes is detected. Two phenotypes, however, showed a sex chromosome effect. In the lateral septum, XY⫺Sry males had a higher (more masculine) density of vasopressin fibers than XXSry males, and XY⫺ females were more masculine than XX females when all-female litters were measured (39). When midbrain cells were harvested from mouse embryos, dissociated and grown in vitro, XY cultures contained more dopamine neurons than XX cultures, regardless of the gonadal type found in the embryo (42). In the latter case, the primary determinant of the sex difference was the genetic sex of cells, not the phenotype of the gonads. These findings suggest that the genetic sex of cells influences the brain phenotype, but it is not clear where the sex chromosome genes act. In the case of the sex chromosome effect on vasopressin fiber density in the lateral septum in vivo, it is possible that sex chromosome complement influences the levels of gonadal secretions some time during development, so that the group differences attributed to the sex chromosomes are explained by well-established laws of hormonal sexual differentiation. This possibility must ultimately be resolved by identifying the X or Y genes responsible for the group difference, and determining how and where they act. Preliminary observations argue against this possibility, however. On most measures of brain sexual phenotype, animals with the same gonadal type, but differing in genetic sex, were not different. Because most of the dependent variables measured are sensitive barometers of the level of gonadal steroids at one or more life stages, a general sex chromosome effect on plasma levels of gonadal steroids would be expected to cause several, not just one sex chromosome effect on the brain phenotype of adults. Other Model Systems Other model systems also allow dissociation of the genetic sex of the brain and gonadal phenotype to test the role of sex 1060 Endocrinology, March 2004, 145(3):1057–1062 Arnold et al. • Minireview FIG. 2. Brain cell phenotypes in mice differing in gonadal sex and complement of sex chromosomes. Adult mice were gonadectomized and treated with equal levels of testosterone. Left, The number of cells expressing tyrosine hydroxylase in the anteroventral periventricular nucleus of the preoptic region (AVPV). Mice with ovaries, irrespective of their complement of sex chromosomes, have fewer cells than mice with testes, suggesting that differences in gonadal secretions account for the sex difference in this adult phenotype (39). Middle, XY⫺Sry adult male mice have a higher (more masculine) density of vasopressinergic fibers in the lateral septum than XXSry male mice, indicating that the complement of sex chromosomes influences this trait (39). XY⫺ female mice are also more masculine on this trait than XX females, not shown. Right shows the number of tyrosine-hydroxylase cells found in cultures of embryonic midbrain cells. XY cultures contain more cells expressing tyrosine hydroxylase than XX cultures, irrespective of the gonadal sex of the embryos from which the cells were taken, illustrating a sex difference attributable to differences in the complement of sex chromosomes (42). *, P ⬍ 0.05. Left and middle panels, Reproduced with permission from Society for Neuroscience 2002 (Ref. 39). Right panel, Based on data from Ref. 42. chromosome genes. For example, XY mice with a weak version of the Y chromosome develop ovaries and differ slightly from XX females in maze learning (43). XX mice carrying several Y genes including Sry have testes, and they differ in their parental behavior from XY males (44). Both of these studies involved testing of gonadally intact animals; thus, group differences are potentially attributed to differences in circulating levels of gonadal steroids at the time of testing, or at earlier times during development. In quail, transplanting female forebrain tissue into the brains of genetically male quail disrupts testis development. Because the testes develop normally in male to male transplants, it appears that a genetically male brain is required for testis development (45). Another approach is to compare mice that are genetically identical except for the strain origin of their Y chromosomes. Such mice show differences in aggression when tested as gonadally intact adults (46 – 49). This result indicates that differences in Y alleles causes differences in aggressive behavior (50) and suggests that the presence or absence of Y genes, as occurs in the male-female comparison, should also influence aggression. As with other genetic approaches, however, that result by itself leaves open the question of whether the Y effect is hormonally mediated. Some mouse strains show Y chromosome effects on plasma levels of androgen (51, 52). With regard to mice showing strain differences in Y-linked aggression, some are found to be similar in their plasma levels of androgen at specific ages but may differ at other ages (53–55). Although measuring plasma levels may in some cases suggest hormonal mediation of a Y effect, the ultimate answer to the question of hormonal mediation will come from identification of the Y genes involved, and their mechanisms of action. The Differences between XX and XY Cells XX and XY cells could be differentiated by Y genes, which are obviously found only in males. Two factors reduce the likelihood of a male-specific effect of Y genes. One is that the Y encodes few proteins [only 27 are predicted to derive from the human Y (56)]. Secondly, many Y genes have a closely homologous X gene (57), which if expressed in female cells will tend to reduce any functional difference between XX and XY cells as long as the pattern of expression is similar to the Y gene. Homologous sex chromosome genes of this sort may not, however, be expressed in parallel (58, 59). More information is needed to assess the importance of male-specific effects of Y genes. A potentially larger source of genetic difference between XX and XY cells is the X chromosome, which is particularly rich in genes important for brain development (60). The sex difference in X dosage is reduced considerably by X-inactivation, the process of transcriptional silencing of one of the two X chromosomes in each non-germline XX cell (61). Some X genes, however, escape inactivation, and therefore could be expressed at a higher dose in females (62). Numerous factors besides genomic dosage control the level of gene expression, so the relationship between inactivation and expression is not well known. Even when an X gene is expressed at a higher level in females, it is not clear whether the sex difference has significant functional consequences. Thus, more information is needed on X gene dosage and its sexspecific effects. XX and XY cells also differ in the source of genomic imprinting of X genes because only XX cells can receive a genomic imprint from the father. In some cases, the genomic imprint is known to produce differences in XX and XY embryos (11, 12). Arnold et al. • Minireview Endocrinology, March 2004, 145(3):1057–1062 1061 Conclusion Based on experiments reviewed here, XX and XY brain cells may have different phenotypes partly because they do not have equivalent genomes. However, only a few experiments have confirmed such differences, in part because of the historical lack of model systems in which a sex chromosome effect can be tested. With regard to sex differences detected in the brain before gonadal differentiation, an important question is whether these differences have a lasting effect on the sexual phenotype of the animal. Are such differences adaptive in the sense that they contribute to functionally important differences in brain phenotype that increase the animal’s sex-specific fitness? An alternative idea is that each species must cope with differences in XX and XY genomes that are the by-product of the commitment of the species to heteromorphic sex chromosomes, and that evolution has favored mechanisms that reduce rather than increase the difference between XX and XY cells (Ref. 63). By this scenario, the differences between XX and XY cells may be small and functionally unimportant and have little impact on the animal’s fitness. In some species such as the zebra finch, however, the neural sex difference discussed here is clearly related to the animal’s ability to reproduce. Assuming that it can be proven that sexual differentiation in this system is triggered by male-female differences in expression of sex chromosome genes, as we currently suspect, this system will provide a clear case of an adaptive sex difference controlled by the genetic sex of brain cells. The new rodent model systems, in which genetic sex and gonadal sex are disentangled, offer significant advantages for studying the role of the sex chromosome genes on brain development. Further advances in the ability to manipulate the genomes of nontraditional model systems, such as songbirds, should allow a test of the role of specific sex chromosome genes to provide stronger evidence of their role in a wider range of organisms. It’s going to be exciting. Acknowledgments Thanks to Robert Agate, Laura Carruth, Paul Burgoyne, Geert De Vries, Emilie Rissman, Richard Simerly, Robin Lovell-Badge, and Amanda Swain for contributions to this work. Received November 4, 2003. Accepted December 5, 2003. Address all correspondence and requests for reprints to: Arthur P. Arnold, Department of Physiological Science, University of California, Los Angeles, 621 Charles E. Young Drive South, Los Angeles, California 90095-1606. E-mail: [email protected]. This work was supported by NIH Grants DC000217, MH59268, NS043196, and NS045966. References 1. Arnold AP 2002 Concepts of genetic and hormonal induction of vertebrate sexual differentiation in the twentieth century, with special reference to the brain. In: Pfaff DW, Arnold AP, Etgen A, Fahrbach S, Rubin R, eds. Hormones, brain, and behavior. San Diego: Academic Press; vol 4:105–135 2. Goodfellow PN, Lovell-Badge R 1993 SRY and sex determination in mammals. Annu Rev Genet 27:71–92 3. Behringer RR 1994 The in vivo roles of Müllerian-inhibiting substance. Curr Top Dev Biol 29:171–187 4. Nordeen EJ, Nordeen KW, Sengelaub DR, Arnold AP 1985 Androgens prevent normally occurring cell death in a sexually dimorphic spinal nucleus. 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