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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
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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
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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.
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