This Article Abstract Full Text (PDF) All Versions of this Article: 145/3/1057    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Arnold, A. P. Articles by Itoh, Y. Search for Related Content PubMed PubMed Citation Articles by Arnold, A. P. Articles by Itoh, Y.

Minireview: Sex Chromosomes and Brain Sexual Differentiation

Department of Physiological Science and Laboratory of Neuroendocrinology of the Brain Research Institute, University of California, Los Angeles, Los Angeles, California 90095

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: arnold{at}ucla.edu.

Abstract

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 hormones. 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.

THE 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 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, 11, 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, 14, 15). The scrotum and mammary tissues are recognizable before gonadal sex is evident. The wallaby example is the clearest case of functionally important sex-specific 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 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 male-specific increase in androgen receptors (25, 26, 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, 29, 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 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, 33, 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 testes-bearing 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.

View larger version (84K): [in this window] [in a new window]   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 ).

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 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 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.

View larger version (19K): [in this window] [in a new window]   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 .

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 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, 47, 48, 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, 54, 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 sex-specific 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).

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.

Footnotes

This work was supported by NIH Grants DC000217, MH59268, NS043196, and NS045966.

Received November 4, 2003.

Accepted for publication December 5, 2003.

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[CrossRef][Medline]
3. Behringer RR 1994 The in vivo roles of Müllerian-inhibiting substance. Curr Top Dev Biol 29:171–187[Medline]
4. Nordeen EJ, Nordeen KW, Sengelaub DR, Arnold AP 1985 Androgens prevent normally occurring cell death in a sexually dimorphic spinal nucleus. Science 229:671–673[Abstract/Free Full Text]
5. Jaeger W 1992 Horner’s law: the first step in the history of understanding X-linked disorders. Ophthalmic Paediatrics Genet 13:49–56
6. Josso N, Cate RL, Picard JY, Vigier B, di Clemente N, Wilson C, Imbeaud S, Pepinsky RB, Guerrier D, Boussin L 1993 Anti-mullerian hormone: the Jost factor. Rec Prog Horm Res 48:1–59
7. Allen E, Danforth CH, Doisy EA, eds. 1938 Sex and internal secretions. 2nd ed. Baltimore: Williams and Wilkins
8. Scott WJ, Holson JF 1977 Weight differences in rat embryos prior to sexual differentiation. J Embryol Exp Morphol 40:259–263[Medline]
9. Pedersen JF 1980 Ultrasound evidence of sexual difference in fetal size in first trimester. Br Med J 281:1253
10. Burgoyne PS 1993 A Y-chromosomal effect on blastocyst cell number in mice. Development 117:341–345[Abstract]
11. Thornhill AR, Burgoyne PS 1993 A paternally imprinted X chromosome retards the development of the early mouse embryo. Development 118:171–174[Abstract]
12. Burgoyne PS, Thornhill AR, Boudrean SK, Darling SM, Bishop CE, Evans EP 1995 The genetic basis of XX-XY differences present before gonadal sex differentiation in the mouse. Phil Trans R Soc Lond B 350:253–260
13. Renfree MB, Short RV 1988 Sex determination in marsupials: evidence for a marsupial-eutherian dichotomy. Phil Trans Royal Soc London B 322:41–53
14. Shaw G, Harry JL, Whitworth DJ, Renfree MB 1997 Sexual determination and differentiation in the marsupial Macropus eugenii. In: Saunders N, Hinds L, eds. Marsupial biology recent research, new perspectives. Sydney, Australia: University of New South Wales Press Ltd.; 132–141
15. Renfree MB, Wilson JD, Shaw G 2002 The hormonal control of sexual development. Novartis Found Symp 244:136–152[Medline]
16. Reisert I, Pilgrim C 1991 Sexual differentiation of monoaminergic neurons—genetic or epigenetic. Trends Neurosci 14:467–473
17. Pilgrim Ch, Reisert I 1992 Differences between male and female brains—developmental mechanisms and implications. Horm Metab Res 24:353–359[Medline]
18. Beyer C, Pilgrim C, Reisert I 1991 Dopamine content and metabolism in mesencephalic and diencephalic cell cultures: Sex differences and effects of sex steroids. J Neurosci 11:1325–1333[Abstract]
19. Dewing P, Shi T, Horvath S, Vilain E 2003 Sexually dimorphic gene expression in mouse brain precedes gonadal differentiation. Brain Res Mol Brain Res 118:82–90[Medline]
20. Arnold AP 1997 Sexual differentiation of the zebra finch song system: positive evidence, negative evidence, null hypotheses, and a paradigm shift. J Neurobiol 33:572–584[CrossRef][Medline]
21. Nottebohm F, Arnold AP 1976 Sexual dimorphism in vocal control areas of the song bird brain. Science 194:211–213[Abstract/Free Full Text]
22. Gurney ME, Konishi M 1980 Hormone-induced sexual differentiation of brain and behavior in zebra finches. Science 208:1380–1382[Abstract/Free Full Text]
23. Gurney ME 1981 Hormonal control of cell form and number in the zebra finch song system. J Neurosci 1:658–673[Abstract]
24. Gahr M, Konishi M 1988 Developmental changes in estrogen-sensitive neurons in the forebrain of the zebra finch. Proc Natl Acad Sci USA 85:7380–7383[Abstract/Free Full Text]
25. Dittrich F, Feng Y, Metzdorf R, Gahr M 1999 Estrogen-inducible, sex-specific expression of brain-derived neurotrophic factor mRNA in a forebrain song control nucleus of the juvenile zebra finch. Proc Natl Acad Sci USA 96:7986–7991[Abstract/Free Full Text]
26. Holloway CC, Clayton DF 2001 Estrogen synthesis in the male brain triggers development of the avian song control pathway in vitro. Nat Neurosci 4:1–7[CrossRef][Medline]
27. Kim Y-H, Perlman WR, Arnold AP Expression of androgen receptor mRNA in the zebra finch song system: developmental regulation by estrogen. J Comp Neurol, in press
28. Arnold AP 2000 Hormonal and non-hormonal mechanisms of sexual differentiation of the zebra finch brain: embracing the null hypothesis. In: Matsumoto A, ed. Sexual differentiation of the brain. New York: CRC Press; 131–148
29. Gahr M, Metzdorf R 1999 The sexually dimorphic expression of androgen receptors in the song nucleus hyperstriatalis ventrale pars caudale of the zebra finch develops independently of gonadal steroids. J Neurosci 19:2628–2636[Abstract/Free Full Text]
30. Grisham W, Arnold AP 1995 A direct comparison of the masculinizing effects of testosterone, androstenedione, estrogen, and progesterone on the development of the zebra finch song system. J Neurobiol 26:163–170[CrossRef][Medline]
31. Wade J 2001 Zebra finch sexual differentiation: the aromatization hypothesis revisited. Microsc Res Tech 54:354–363[CrossRef][Medline]
32. Wade J, Arnold AP 1996 Functional testicular tissue does not masculinize development of the zebra finch song system. Proc Natl Acad Sci USA 93:5264–5268[Abstract/Free Full Text]
33. Springer ML, Wade J 1997 The effects of testicular tissue and prehatching inhibition of estrogen synthesis on the development of courtship and copulatory behavior in zebra finches. Horm Behav 32:46–59[CrossRef][Medline]
34. Wade J, Gong A, Arnold AP 1997 Effects of embryonic estrogen on differentiation of the gonads and secondary sexual characteristics of male zebra finches. J Exp Zool 278:405–411[CrossRef][Medline]
35. Agate RJ, Grisham W, Wade J, Mann S, Wingfield J, Schanen C, Palotie A, Arnold AP 2003 Neural not gonadal origin of brain sex differences in a gynandromorphic finch. Proc Natl Acad Sci USA 100:4873–4878[Abstract/Free Full Text]
36. Schlinger BA, Soma KK, London S 2001 Neurosteroids and brain sexual differentiation. Trends Neurosci 24:429–431[Medline]
37. Lovell-Badge R, Robertson E 1990 XY female mice resulting from a heritable mutation in the primary testis-determining gene, Tdy. Development 109:635–646[Abstract]
38. Mahadevaiah SK, Odorisio T, Elliott DJ, Rattigan A, Szot M, Laval SH, Washburn LL, McCarrey JR, Cattanach BM, Lovell-Badge R, Burgoyne PS 1998 Mouse homologues of the human AZF candidate gene RBM are expressed in spermatogonia and spermatids, and map to a Y chromosome deletion interval associated with a high incidence of sperm abnormalities. Hum Mol Genet 7:715–727[Abstract/Free Full Text]
39. De Vries GJ, Rissman EF, Simerly RB, Yang LY, Scordalakes EM, Auger CJ, Swain A, Lovell-Badge R, Burgoyne PS, Arnold AP 2002 A model system for study of sex chromosome effects on sexually dimorphic neural and behavioral traits. J Neurosci 22:9005–9014[Abstract/Free Full Text]
40. Markham JA, Jurgens HA, Auger CJ, De Vries GJ, Arnold AP, Juraska JM 2003 Sex differences in mouse cortical thickness are independent of the complement of sex chromosomes. Neuroscience 116:71–75[CrossRef][Medline]
41. Wagner CK, Xu J, Pfau JL, Quadros PS, De Vries GJ, Arnold AP 2004 Neonatal mice possessing an Srytransgene show a masculinized pattern of progesterone receptor expression in the brain independent of sex chromosome status. Endocrinology 145:1046–1049[Abstract/Free Full Text]
42. Carruth LL, Reisert I, Arnold AP 2002 Sex chromosome genes directly affect brain sexual differentiation. Nat Neurosci 5:933–934[CrossRef][Medline]
43. Stavnezer AJ, McDowell CS, Hyde LA, Bimonte HA, Balogh SA, Denenberg VH 2000 Spatial ability of XY sex-reversed female mice. Behav Brain Res 112:135–143[CrossRef][Medline]
44. Reisert I, Karolczak M, Beyer C, Just W, Maxson SC, Ehret G 2002 Sry does not fully sex-reverse female into male behavior towards pups. Behav Genet 32:103–111[CrossRef][Medline]
45. Gahr M 2003 Male Japanese quails with female brains do not show male sexual behaviors. Proc Natl Acad Sci USA 100:7959–7964[Abstract/Free Full Text]
46. Maxson SC 1999 Sex differences in genetic mechanisms for mammalian brain and behavior. Biomed Rev 7:85–90
47. Maxson SC, Didier-Erickson A, Ogawa S 1989 The Y chromosome, social signals, and offense in mice. Behav Neural Biol 52:251–259[CrossRef][Medline]
48. Maxson SC, Ginsburg BE, Trattner A 1979 Interaction of Y-chromosomal and autosomal gene(s) in the development of intermale aggression in mice. Behav Genet 9:219–226[CrossRef][Medline]
49. Guillot PV, Carlier M, Maxson SC, Roubertoux PL 1995 Intermale aggression tested in two procedures, using four inbred strains of mice and their reciprocal congenics: Y chromosomal implications. Behav Genet 25:357–360[CrossRef][Medline]
50. Sluyter F, Van Oortmerssen GA, De Ruiter AJH, Koolhaas JM 1996 Aggression in wild house mice: current state of affairs. Behav Genet 26:489–496[CrossRef][Medline]
51. Tordjman S, Roubertoux PL, Carlier M, Moutier R, Anderson G, Launay M, Degrelle H 1995 Linkage between brain serotonin concentration and the sex-specific part of the Y-chromosome in mice. Neurosci Lett 183:190–192[CrossRef][Medline]
52. Jutley JK, Stewart AD 1986 Genetic analysis of the Y-chromosome of the mouse: evidence for two loci affecting androgen metabolism. Genet Res 47:29–34[Medline]
53. Selmanoff MK, Goldman BD, Ginsburg BE 1977 Developmental changes in serum luteinizing hormone, follicle stimulating hormone and androgen levels in males of two inbred mouse strains. Endocrinology 100:122–127[Abstract]
54. Selmanoff MK, Goldman BD, Maxson SC, Ginsburg BE 1977 Correlated effects of the Y-chromosome of mice on developmental changes in testosterone levels and intermale aggression. Life Sci 20:359–365[CrossRef][Medline]
55. Guillot PV, Roubertoux PL, Degrelle H, Carlier M, Phillips J, Maxson SC 1993 Y chromosome and adult plasma testosterone levels in mice. Behav Genet 23:553
56. Skaletsky H, Kuroda-Kawaguchi T, Minx PJ, Cordum HS, Hillier L, Brown LG, Repping S, Pyntikova T, Ali J, Bieri T, Chinwalla A, Delehaunty A, Delehaunty K, Du H, Fewell G, Fulton L, Fulton R, Graves T, Hou SF, Latrielle P, Leonard S, Mardis E, Maupin R, McPherson J, Miner T, Nash W, Nguyen C, Ozersky P, Pepin K, Rock S, Rohlfing T, Scott K, Schultz B, Strong C, Tin-Wollam A, Yang SP, Waterston RH, Wilson RK, Rozen S, Page DC 2003 The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 423:825–837[CrossRef][Medline]
57. Jegalian K, Page DC 1998 A proposed path by which genes common to mammalian X and Y chromosomes evolve to become X inactivated. Nature 394:776–780[CrossRef][Medline]
58. Xu J, Burgoyne PS, Arnold AP 2002 Sex differences in sex chromosome gene expression in mouse brain. Hum Mol Genet 11:1409–1419[Abstract/Free Full Text]
59. Agate RJ, Choe MC, Arnold AP Sex differences in structure and expression of the sex chromosome genes CHDZ and CHDW in zebra finches. Mol Biol Evol, in press
60. Zechner U, Wilda M, Kehrer-Sawatzki H, Vogel W, Fundele R, Hameister H 2001 A high density of X-linked genes for general cognitive ability: a run-away process shaping human evolution? Trends Genet 17:697–701[CrossRef][Medline]
61. Lyon MF 1999 X-chromosome inactivation. Curr Biol 9:R235–R237
62. Carrel L, Cottle AA, Goglin KC, Willard HF 1999 A first-generation X-inactivation profile of the human X chromosome. Proc Natl Acad Sci USA 96:14440–14444[Abstract/Free Full Text]
63. De Vries GJ 2004 Minireview: sex differences in adult and developing brains: compensation, compensation, compensation. Endocrinology 145:1063–1068[Abstract/Free Full Text]

This article has been cited by other articles:

				J. Xu, X. Deng, R. Watkins, and C. M. Disteche Sex-Specific Differences in Expression of Histone Demethylases Utx and Uty in Mouse Brain and Neurons J. Neurosci., April 23, 2008; 28(17): 4521 - 4527. [Abstract] [Full Text] [PDF]

				H. B. Patisaul, A. E. Fortino, and E. K. Polston Sex Differences in Serotonergic But Not {gamma}-Aminobutyric Acidergic (GABA) Projections to the Rat Ventromedial Nucleus of the Hypothalamus Endocrinology, January 1, 2008; 149(1): 397 - 408. [Abstract] [Full Text] [PDF]

				C A Wilson and D C Davies The control of sexual differentiation of the reproductive system and brain Reproduction, February 1, 2007; 133(2): 331 - 359. [Abstract] [Full Text] [PDF]

				R. C. Knickmeyer and S. Baron-Cohen Topical Review: Fetal Testosterone and Sex Differences in Typical Social Development and in Autism J Child Neurol, October 1, 2006; 21(10): 825 - 845. [Abstract] [PDF]

				X. Chen, R. J. Agate, Y. Itoh, and A. P. Arnold Sexually dimorphic expression of trkB, a Z-linked gene, in early posthatch zebra finch brain PNAS, May 24, 2005; 102(21): 7730 - 7735. [Abstract] [Full Text] [PDF]

				J. D. Blaustein Can You Teach an Old Dogma New Tricks? Endocrinology, March 1, 2004; 145(3): 1055 - 1056. [Full Text] [PDF]

				G. J. De Vries Minireview: Sex Differences in Adult and Developing Brains: Compensation, Compensation, Compensation Endocrinology, March 1, 2004; 145(3): 1063 - 1068. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 145/3/1057    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Arnold, A. P. Articles by Itoh, Y. Search for Related Content PubMed PubMed Citation Articles by Arnold, A. P. Articles by Itoh, Y.