Sexual dfferentiationin human embryologythe process by which the male and female sexual differentiation develop from neutral embryonic structures.
The normal human fetus of either sex has the potential to develop either male or female organs, differentiation on genetic and hormonal influences. In humans, each egg contains 23 chromosomesof which 22 are autosomes and 1 is a female sex chromosome the Sex chromosome. Each sperm also contains 23 chromosomes: 22 autosomes and differetniation one female sex chromosome or one male sex chromosome the Y chromosome.
An egg that has been fertilized has a full complement of 46 chromosomes, of which two are sex chromosomes. Therefore, differenitation sex of the individual is determined at the time of fertilization ; fertilized eggs containing an XY sex chromosome complement are genetic males, whereas sex containing an XX sex chromosome complement are differentkation females.
Every fetus contains structures that are capable of developing into either male or female genitalia, and, regardless of the complement of sex chromosomes, all developing differentiatoon become feminized unless masculinizing influences come sex play at key times during gestation. In males, several testis -determining genes on the Y chromosome differentoation the differentiation undifferentiated indeterminate embryonic gonads to develop as testes. The X chromosome also participates in the differentiating sex, because two X chromosomes are necessary for the development of normal ovaries.
In addition, the Wolffian ducts are stimulated by testosterone to sex develop into the spermatic ducts ductus deferensejaculatory ducts, and seminal vesicles. If the fetal gonads do not secrete testosterone at the proper time, the genitalia develop in the female direction regardless of whether testes or sex are present. Sexual differentiation is completed at pubertyat which time the reproductive system in both women and men is mature.
In such a complex system there are differentiation opportunities for aberrant development. The causes of disorders of sexual differentiation, while not fully understood, have been greatly elucidated by advances in chromosomal analysis, the identification of isolated genetic defects in steroid hormone synthesis, and the understanding of abnormalities in steroid hormone receptors.
For more information about the embryological and anatomical aspects of diffetentiation gonads and genitalia, see human reproductive system. For descriptions of chromosomes and the genes that they carry, see human genetics. Sexual differentiation. Info Print Cite. Submit Feedback. Thank you for your feedback. Sexual differentiation embryology. Written By: Robert D. See Article History.
Read More on This Topic. Differentiation between the sex exists, therefore, as the primary difference represented by the distinction sex eggs differentiation sperm, differentiation. Differentiatioh today for unlimited access differentistion Britannica. Learn More in these related Britannica articles:. Differentiation between the sexes exists, therefore, as the primary difference represented by the distinction between eggs and sperm, by differences represented by nature of the differentiation glands and their associated structures, and lastly by differences, if any, between individuals diffdrentiation the male and female reproductive….
Sexual dex of the fetus into a male or a female is difgerentiation controlled by delicately timed hormonal changes. Following birth and a period of steady growth in infancy and childhood, the changes associated with puberty and adolescence take place. This dramatic transformation of an…. Embryologythe study of the formation and development of an embryo and fetus. Before widespread use of the microscope and the advent of cellular biology in the 19th century, embryology was based on descriptive and comparative studies.
From the time divferentiation the Greek philosopher Aristotle it was debated whether the…. History differentiation your fingertips. Sign up here to see what happened On This Dayevery day in your inbox! By signing up, sex agree to our Privacy Notice. Be on the lookout for your Britannica newsletter to get trusted stories delivered right to your inbox. More Differentiation.
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In such cases, it is not always possible to tell right away differentiate whether the baby is a boy or a girl. In the past, disorders of sex differentiation were given names such as intersex or sex. That leaves the sex assignment unclear or a mixture of both male and female. There are different types of DSD and each type has a different cause. The most common DSD types in children include:.
The tissue that eventually turns into testes or ovaries is present early in fetal development. Sexual organ development is influenced by differrentiation chromosomeshormones, and environmental factors. Differentiation cause of a DSD is not differentiation known. The sex of a Sex depend on the type of condition. In general, genitals that are not typical indicate a DSD. However, a DSD can sometimes be found only internally.
Cleveland Clinic is a non-profit academic sex center. Advertising on our site helps support our differentiation. We do not endorse non-Cleveland Clinic products differentiation services.
Disorders of Sex Differentiation Disorders of sexual differentiation occur when a baby is born with both male and female sex organs. What are disorders of sex differentiation DSD? What are the types differentiation disorders of sex differentiation DSD? Differentiation may be male or ambiguous not having a clear sex. The child may differentiatjon an enlarged differentiation a female sex organ that looks like a penis. The lower section of the vagina may be closed.
A child with CAH does not have a specific enzyme that sex body differebtiation to make the hormones cortisol and aldosterone. Without these sex hormones, the body produces more androgens male sex hormones.
If the affected child is female, the high androgen levels before birth sex the genitals to become more male in appearance. This condition can cause serious health issues later on, such as life-threatening kidney problems differentuation need to be treated as soon as possible.
Female with male chromosomes 46, Cifferentiation DSD : Some female children have male chromosomes XY but their external genitals may appear entirely female or unclear. In addition, the womb may or may not be present. The testicles may be absent or not properly formed. Several different causes are behind this condition.
Androgen insensitivity syndrome AIS is sex eifferentiation cause. With AIS, differentiation body either ignores androgens or is not sensitive to them. For this reason, the child appears to be female.
The testes usually remain inside the body and the womb does not develop. Mixed genitals and sex organs 46, XX Ovotesticular : This is a very rare type of DSD where the child difderentiation tissue from both ovaries and testicles.
The genitals may appear female, male, or a mix of both. Children with this type of DSD have female chromosomes. Although the cause of this condition is not known, some cases have been linked to genetic material normally differentiation on the Y chromosome that is misplaced on the X chromosome.
Sex chromosome DSD : Some children have neither male nor female chromosomes. Their sex organs are, however, normally formed as either male or female. Those children may not go differentiation normal sexual development at puberty. For example, a child with female sex organs may not start sex periods, and may have small breasts. Rokitansky syndrome : Some females are born without a womb, cervix, and upper vagina.
Some may have underdeveloped organs. In this condition, the ovaries and external genitalia vulva are still present. They will still develop breasts and pubic hair as they get older. The cause of Rokitansky syndrome is not clear.
Girls and women with this condition have normal XX chromosomes. Sex first sign of Rokitansky syndrome is sex a girl does not start having periods. Sex may also be difficult because the vagina is shorter than normal. Women with Rokitansky syndrome sex have no womb cannot become pregnant. It is sometimes possible to take eggs from the individual to make a surrogate pregnant. What are the causes of a disorder of sex differentiation DSD?
What are the symptoms of a disorder of sex differentiation DSD? Show More.
Introduction: History and Definitions
The X chromosome also participates in the differentiating process, because two X chromosomes are necessary for the development of normal ovaries. In addition, the Wolffian ducts are stimulated by testosterone to eventually develop into the spermatic ducts ductus deferens , ejaculatory ducts, and seminal vesicles.
If the fetal gonads do not secrete testosterone at the proper time, the genitalia develop in the female direction regardless of whether testes or ovaries are present. Sexual differentiation is completed at puberty , at which time the reproductive system in both women and men is mature. In such a complex system there are many opportunities for aberrant development. The causes of disorders of sexual differentiation, while not fully understood, have been greatly elucidated by advances in chromosomal analysis, the identification of isolated genetic defects in steroid hormone synthesis, and the understanding of abnormalities in steroid hormone receptors.
For more information about the embryological and anatomical aspects of the gonads and genitalia, see human reproductive system. For descriptions of chromosomes and the genes that they carry, see human genetics. Sexual differentiation. Info Print Cite. Submit Feedback. Thank you for your feedback. Sexual differentiation embryology. Written By: Robert D. See Article History. Read More on This Topic. Differentiation between the sexes exists, therefore, as the primary difference represented by the distinction between eggs and sperm, by….
Subscribe today for unlimited access to Britannica. Learn More in these related Britannica articles:. These factors act in parallel and in combination to induce sex differences. They can also can offset each other to reduce sex differences. Other mechanisms, operating at the level of populations, cause groups of males to differ on average from groups of females. The theory has advantages for directing attention to inherent sex-biasing factors that operate in many tissues to cause sex differences, to cause sex-biased protection from disease, and to frame questions for further study.
The study of sexual differentiation has undergone dramatic changes in the last half century. Before , investigators in this field had predominantly studied the most obvious phenotypic sex differences, in the gonads, external and internal genitalia, and behavior Arnold, These investigators viewed themselves largely as reproductive biologists and psychologists, because of the function of the tissues or behaviors they studied.
Earlier in the 20 th century, investigators had asked the fundamental question whether phenotypic sex differences were dictated by the sex chromosomes or by gonadal secretions Allen, ; Young, For the birds and mammals, the answer was that sexual development outside the gonads was controlled by gonadal hormones. Experiments showed that changing the gonadal hormones could profoundly change the sexual phenotype of reproductive tissues other than the gonads.
For example, it was possible to give male hormones to genetic XX females to make the genitals or behavior similar to that of a male, or to take male hormones away from genetic XY males to make their genitals and behavior like that of females Jost, By the s, the central idea of 20 th Century sexual differentiation theory was accepted, even though the most definitive experiments were done later, for example by Jost Jost et al.
Phoenix et al. Once the gonads differentiate as testes or ovaries, however, their hormonal secretions determine the sexual phenotype of the rest of the body and behavior sexual differentiation. This simple dichotomization of the sexual differentiation process genetic sex determination followed by hormonal sexual differentiation of non-gonadal tissues is no longer tenable based on recent experimental results Arnold, ; McCarthy and Arnold, , but persists in the literature on sex determination.
In the theory summarized here, all biological sex differences in gonadal and non-gonadal tissues are seen as downstream from the inherent sexual inequality in the sex chromosomes Arnold, Several developments have contributed to a revision of the old dogma.
One is that the revolution in molecular genetics has given us a much better understanding of the genes on the sex chromosomes, their evolution, and function Deng et al. This new knowledge shows that the inherent inequality of X and Y genetic material in the two sexes has effects throughout the body, not just on the gonads. A second major influence has been that various experimental findings have uncovered cases in which the old theory was inadequate.
These include studies of tamar wallabies, in which some non-gonadal sexual tissues develop differently in the two sexes before the gonads differentiate Renfree and Short, Their sexual differentiation cannot be caused by sex differences in gonadal secretions.
In studies of songbirds, various examples were discovered in which the sexual phenotype of non-gonadal tissues, including the brain, did not correlate with the type of gonads, but did correlate with the type of sex chromosomes Agate et al. The studies in songbirds, at least in our own lab, catalyzed a shift to study of mice in which the complement and number of sex chromosomes could be manipulated without changing the type of gonad Burgoyne et al. Extensive studies of mice leave no doubt that the complement of sex chromosomes has direct effects outside the gonads, including on the brain, to cause sex differences Arnold et al.
At the same time as these developments, the study of sex differences was expanding beyond tissues related to reproduction. Especially since , there has been increasing realization that sex differences occur throughout the body.
Tissues not specialized for reproduction, including non-reproductive areas of the brain, function differently in females and males, and are differentially affected by disease in the two sexes US National Institute of Medicine Committee on Understanding the Biology of Sex and Gender Disorders, In some cases, sex differences in disease can be dramatic, as in systemic lupus erythematosus SLE , which occurs nine times more often in women than men, or autism spectrum disorder which occurs 2—4 times more often in boys and men than in females.
When striking sex differences occur, any fundamental understanding of the disease requires understanding of the causes and consequences of sex differences the disease.
To explain sex differences in disease, one turns to the theory of sexual differentiation, which enumerates and classifies inherent factors that differ in the two sexes, suggesting experiments that can be performed to uncover the origins for any sex difference.
Moreover, a sex difference in disease means that one sex is protected from the disease more than the other. This fact provides a rationale for discovering the sex-biasing factors that are protective or harmful, as part of a strategy for discovery of novel protective factors that might be targets of therapy.
If testosterone protects from a disease, for example, then understanding the downstream genes regulated by testosterone might point to previously unknown gene pathways that are protective and could be drug targets. This information is potentially useful for both sexes. In mammals and birds, sex differences originate in the genome, at the time of conception.
However, beginning at birth, the human infant is placed into a highly gendered social and physical environment. Boys and girls are expected and required to behave differently. They choose different occupations and life paths, on average, with differences in physical and emotional stress, diet, and much more Kishi et al. The large sex differences in environment no doubt contribute to sex differences in function of the brain, and in incidence and progression of diseases.
For example, occupations chosen more often by one sex may create specific types of stress that make that sex more susceptible to certain maladies. Moreover, it is likely that different environments experienced by females and males interact with the biological sex differences in individuals.
The social and biological factors can augment each other e. Specific environments may cancel out sex-biasing effects of gonadal hormones more in some brain regions than in others, reducing sex differences in a brain region-specific manner Joel et al.
At this point in history, however, this is as much a reasoned statement of belief as a well-documented phenomenon. One reason is that biological factors typical of one sex co-vary with social factors typical of that sex, so that it can be impossible to gauge their relative importance or even independent effects on a trait.
Another reason is that biological and environmental factors change each other. A knock out of the androgen receptor in XY individuals CAIS, Complete Androgen Insensitivity Syndrome in humans alters the body so that it looks completely like that of a female, proving that the masculine structure of many reproductive tissues requires androgen action in males.
However, because the XY CAIS girl is reared as a female, one cannot easily separate the biologically and socially mediated effects of the mutation on many attributes that one might measure in CAIS women, for example their brain function or susceptibility to disease e.
In addition, differences in social or physical environments are expected to have lasting effects on the epigenome DNA methylation and modifications of histones , so that the environment alters the read-out of the genome Szyf et al.
Much of the argument, about whether social or biological factors cause sex differences in physiology and disease, may be based as much on which factors a specific author finds to be interesting or preferable, rather than on any evidence that effects of one factor can be dissociated from effects of others and found to be more important.
The environmentalist and biologist are both susceptible to the mistake of overgeneralizing the importance of factors that they are trained to study or prefer. The theory of sexual differentiation, presented below, focuses exclusively on the biological factors that make females and males different from each other.
This focus comes with the acknowledgement that sex-biasing factors are also found in the social and physical environments. Differentiation, a concept of developmental biology, suggests a change in cells and tissues during ontogeny. Cells lose pluripotency and commit irreversibly to a differentiated fate. A slightly different connotation stems from the idea that any sex difference, at any life stage, can be seen as the result of sexual differentiation, even if that difference is reversible or impermanent.
These ideas underlie the organizational - activational dichotomy of Phoenix et al. Because sex-biasing factors androgens, estrogens, etc.
In my view, all factors that cause sex differences need to be subsumed in a theory of sexual differentiation, because even transient sex differences are sexually differentiated and controlled by inherent sex differences in the genome.
Indeed, such transient effects of gonadal hormones may be the most potent proximate factors that make male and female tissues different. Several considerations make it advantageous to articulate a general theory of sexual differentiation. This generality is useful, because studies of mechanisms of sexual differentiation in one tissue will suggest concepts to be tested in other tissues. Current theory will likely be incomplete or false, and will be improved by future research.
One view is that sexual differentiation is only studied within the confines of other traditional disciplines. Sexual differentiation of the brain is studied within Neuroscience, and sexual differentiation of obesity is studied within the field of Metabolism. Because common mechanisms sexually differentiate brain and adipose tissues, results in one traditional discipline illuminate the general theory of sexual differentiation applied to any tissue.
The theory of sexual differentiation links studies across traditional disciplines, and forms a set of ideas that are tested within the discipline of Sexual Differentiation. The theory suggests questions that might not be framed by other disciplinary perspectives. The sexual differentiationist studying obesity asks different questions Arnold et al. These methods include the manipulation of sex chromosomes and gonadal hormonal to discover their effects at each level.
Those oversimplifications were accepted in part because they were heuristically pleasing. It made sense that only two male hormones coordinate sexual development so that different parts of the body were uniformly male or female. A more accurate model, proposed here, still allows a pleasing simplification, which is that all sex differences derive from the inherent inequality in the sex chromosomes Arnold, Although this theory is more complex, and implies that multiple, parallel-acting and interacting sex-biasing factors contribute to the sexual differentiation of tissues, it nevertheless still provides a simplifying conceptual framework for a complex set of phenomena.
In species with heteromorphic sex chromosomes mammals, birds, etc. In mammals, females have two X chromosomes and males have one, and males have a Y chromosome lacking in females. The differential representation of X and Y genetic material is the sole source of all subsequent sex differences during development and adulthood, because all other factors autosomal genes, cytoplasmic material, prenatal environment of the zygote are thought to be equivalent, on average, between males and female zygotes.
The Y-encoded Sry gene initiates masculine differentiation of the gonads, making gonadal hormones different in males compared to females, thus indirectly causing major sex differences in tissue function. Sry causes relatively undifferentiated gonadal tissue to commit to a testicular fate Koopman, In the absence of Sry in females, X-linked or autosomal genes, which unlike Sry are not inherently sexually different in their representation in the genome, initiate ovarian development.
Thus, Sry present vs. Gonadal differentiation sets up life-long sex differences in the plasma levels of gonadal steroid hormones such as testosterone, estradiol, and progesterone, which act throughout the body at multiple life stages to make tissues of one sex different from the other. It is thought that these hormonal factors cause the majority of sex differences in the brain McCarthy and Arnold, but see below.
The Y chromosome has cell-autonomous effects outside of the gonads that make Y-bearing cells different from those lacking a Y chromosome.
Examples are as follows: Sry acts directly within the brain to make it function differently Czech et al. Other Y genes have an inherently male function because they act on germ cells in a cell-autonomous fashion and are required for spermatogenesis, a male-specific function Burgoyne and Mitchell, Other Y genes or genetic regions also likely contribute to sex differences in autoimmune disease Case et al.
The presence of two or more X chromosomes triggers the expression of the long noncoding RNA Xist from one of the two X chromosomes, thereby making all such cells different from those with one X chromosome. Xist initiates the transcriptional silencing of that chromosome, which does not occur in any XY cells.
Xist has not, however, traditionally been considered a sex-determining or sex-differentiating gene, despite it profound female-specific effects on cells. Instead, X inactivation has long been viewed as a process that reduces sex differences, because X genes are expressed from a single X chromosome in XX cells, as in XY cells. This process allows the cell to avoid higher expression of most X genes in cells with two X chromosomes instead of one. However, X-inactivation leaves the XX cell inherently different from the XY cell, and therefore ranks as one of the most important genes of sexual differentiation.
At the very least, when XX and XY cells have similar function that is influenced by the level of expression of an X gene, the cellular mechanisms leading to sexual equivalence of XX and XY cells are different in the two types of cell. In addition, although it has been speculated that Xist might have female-specific effects on autosomes, such trans effects are not known. Sex differences in gene expression also arise because some X genes escape X inactivation and are expressed from both chromosomes in XX cells so that expression is inherently higher in XX cells than XY cells Disteche, This higher expression is likely to cause sex differences in phenotypes.
XX cells have X chromosomes and imprints from both parents, but XY cells receive only the X imprint from the mother. This could cause a sex difference in the expression of the imprinted gene in either direction Babak et al. For example, an X gene that is silenced when inherited from the mother will be expressed higher in XX than XY, but a gene silenced when inherited from the father will be expressed higher in XY than XX tissues.
Some evidence suggests that the presence of a large heterochromatic X chromosome in XX but not XY cells could have indirect effects on expression of autosomal genes. These putative effects in mammals extend earlier findings of sex-specific heterochromatin Drosophila , in which the large heterochromatic Y chromosome has epigenetic effects not effects of Y gene expression , which regulates many autosomal genes, especially those involved in mitochondrial function and immune response Lemos et al.
Recent evidence indicates that sexually differentiated mechanisms underlie phenotypes that are quite similar in the two sexes Arnold, ; De Vries, In some cases, an unavoidable inherent sex difference in cells causes a sex difference that is not adaptive. New sex-specific forces evolve that counteract or reduce the effect of the maladaptive sex difference, producing greater sexual equality of phenotype.
Because disease or environmental factors can increase or decrease the individual counteracting sex-biasing factors, they can change how much compensation occurs.
In this manner, phenotypes that are balanced in the two sexes can diverge under specific disease or environmental conditions. The main theory describes sex-biasing factors that are inherently different in XX vs.
XY cells and tissues, which operate during ontogeny of all individuals to differentiate the two sexes. These ontogenetic mechanisms should be discoverable in inbred strains of laboratory animals such as mice. In addition to these mechanisms, groups of females and males can differ on average because of population-level forces that act differentially on the two sexes. The population-level differences, however, are unlikely to be modeled well in inbred strains because they require genetic heterogeneity that has been bred out of inbred strains.
Because most males have one X chromosome, any variant of X alleles has greater impact than in females, who have two alleles whose effects are more or less averaged.
A well-known example of a sex difference is red-green color blindness, caused by a variation in the X-linked opsin gene, which shifts the spectral sensitivity of cones in the retina. The shift is experienced more by males, because of hemizygous exposure of the X allele.
Females carrying the mutation are less likely to experience the color blindness because they have a second X allele that does not shift the spectrum of photosensitivity, so that they can discriminate red from green. The resulting male bias in many X-linked diseases is well known and has long been appreciated, and has been suggested to contribute to the overall lower survival of males Migeon, However, more subtle variations in X alleles, not causing disease, no doubt increase the incidence of sex differences in phenotypes via the same mechanism operating in populations of males and females.
XX tissues are inherently mosaics, because they are composed of a mixture of cells in which the active X chromosome is either maternal or paternal.
The two X chromosomes differ both in their alleles different variants inherited from the two parents and in their parental imprints. The mosaicism could cause differences in tissue function, compared to that in males. Generally, tissues that have two different populations of cells might function differently than tissues that have only a single population.
An example is that the two types of cells may be in competition during ontogeny. This process has been modeled in mice with a heterozygous knock out of the X-linked Hccs gene Drenckhahn et al. Early in embryonic life of these mice, the heart is a mixture of cells in which the active X chromosome is from either parent, with both the null or WT allele of Hccs.
By the time of birth, however, the WT allele is found to be expressed in the majority of cardiac cells, indicating a competitive advantage of the WT Hccs locus.
Under these conditions, the mosaicism of the XX tissues actually widens the sexual inequalitty in effects of the mutation, so that males are either mutant dead or not, but females can compensate developmentally for the inheritance of a weak allele and reduce its effect.
If the protection is complete, with complete loss of the disease allele during development, then females never experience detrimental effects of the disease allele. It is also likely that some autosomal alleles are more adaptive in one sex than the other, leading to embryonic sex-specific or sex-biased functions or diseases.
For example, some alleles might not be compatible with male levels of testosterone. Such alleles would drop out of the population of males early in their lifetime because of embryonic lethality , whereas other alleles might drop out of the population of females because of sensitivity to female-enhanced factors. Thus, populations of males and females may differ on average in their complement of autosomal alleles, which would shift the mean phenotype of males and females away from each other.
Sex-biased evolutionary forces may produce a loss of viability disproportionately in the two sexes. The mitochondrial genome is inherited through the female lineage from mother to daughter. This could allow mitochondrial alleles to be selected that are beneficial to females but deleterious to males, because the disadvantage to males never results in differential fitness of the females who pass down the genes.
Such variations in mitochondrial genes would give rise to greater disease or developmental defects primarily affecting males. Evidence from experimental studies of Drosophila support the existence of this phenomenon. When mitochondria from one strain were bred onto different nuclear genetic background strains, males were disproportionately affected, with male-specific decreases in viability Innocenti et al. Such a mechanism, operating in natural populations, may increase the disease burden on males and produce population-level sex differences in disease incidence.
Although there is ample evidence for effects of gonadal hormones that cause sexual differentiation, much of the theory articulated above has not been tested extensively. Many of the ideas leading to the theory come from analysis of the X and Y chromosomes and their effects on cells in vitro , where it can be demonstrated that the inequality of X and Y chromosomes causes sex differences in gene expression or other cell-level phenotypes.
What is not very clear, at the present time, is how important each of the sex-biased mechanisms is, for whole-organ or organismal physiology and disease. For example, a few studies indicate that inequality in the number of X chromosomes contributes to sex differences in disease models in mice Arnold et al. In mouse models of obesity, cardiovascular disease, and sex chromosome aneuploidy, mice with two X chromosomes have worse disease outcomes than mice with one X chromosome.
However, there are no studies to date that have determined which of the four X-chromosome based mechanisms 3ABCD discussed above account for the different effects of one vs. This is an important area for future research. The growing appreciation of the importance of sex chromosome effects in mammals, not mediated by gonadal hormones, has been possible because of experiments on a few mouse models, in which the complement of sex chromosomes XX vs.
XY can be manipulated without changing the type of gonad. These models will be used increasingly to uncover further cases in which sex chromosome complement contributes to sex differences in physiology.
However, these models give only information about mice, and are therefore are best suited to phenomena that can be discovered in mice. It would be advantageous to develop other animal models in which specific sex-biasing mechanisms, enumerated above, are manipulated to mimic the difference that occurs in females vs. For example, comparing animals with one vs. With improved methods for manipulation of the genome in diverse animal groups, this kind of experiment may become increasingly feasible in informative animal systems.
The theory articulated here involves almost no discussion of the role of epigenetic effects, long non-coding RNAs, and microRNAs, because little is known at this point in history. The theory is expected to be greatly enriched by future studies in this area. For example, both gonadal hormones and sex-biased sex chromosome genes are known regulators of DNA methylation and histone modifications Berletch et al.
There has been no systematic discovery of sexual differentiation of noncoding RNAs that regulate many other genes, but that situation is likely to change in the near future Reinius et al. Sex-biasing factors need to be understood in a larger evolutionary framework.
The genes escaping X inactivation mechanism 3B , for example, sometimes have a very closely related gene on the Y chromosome, which has very similar DNA sequence and function Lahn and Page, These X-Y gene pairs are both derived from a common ancient precursor. As the Y chromosome lost most of its genes during evolution, a few terribly important genes were highly resistant to deletion. These Y gene were retained to balance the effects of the X paralogous genes, so that females have two copies one on each X chromosome , and males have two copies one X and one Y Bellott et al.
Patterns of sex chromosome evolution therefore imply that the X-Y partner genes have similar function. In contrast, recent studies suggest that the X and Y forms have at least partly diverged in their functions Shpargel et al. These discoveries mean that the sex-biasing effects of one vs. More information is needed to resolve the importance of these genes in sexual differentiation. Point 4 of the theory elevates the importance of interactions of diverse sex-biasing factors.
Natural selection can either favor the evolution of sex-biased mechanisms to produce sex differences that are adaptive, or to offset other sex differences when they are maladaptive.
Although we are just beginning to appreciate the complex interactions that require or involve such compensation, we have almost no information about which sex-biased effects interact with others. In the study of metabolism and obesity, for example, estrogens reduce body weight and body fat in female mice Foryst-Ludwig and Kintscher, , but a second X chromosome increases body weight and fat Chen et al.
In both cases, no studies have yet to manipulate sex chromosome complement and hormonal status at the same time, to begin to unravel the molecular mechanisms leading to the interactions. It is possible that each factor estradiol and an X chromosome gene acts on the same or different molecular pathways to affect physiology and disease, or that they act on completely separate tissues, cells, or cellular functions, to influence an emergent phenotype revealed by system-level measurements of disease.
In other systems, sex chromosome complement acts on two different tissues in the same disease.
NCBI Bookshelf. Endotext [Internet]. Rodolfo ReyM. Genital sex differentiation involves a series of events whereby the sexually indifferent embryo progressively acquires male differentiation female characteristics in the gonads, genital tract and external genitalia.
Normal sex development consists of several sequential stages. Genetic sex, as determined by the chromosome constitution, drives the primitive gonad to differentiate into a testis or an ovary. Subsequently, internal and external genitalia will follow the male pathway in the presence of specific testicular hormones, or the female pathway in their absence.
Since the presence of the fetal testis plays a determining role in the differentiation of the reproductive tract, the term "sex determination" has been coined to designate the differentiation of the gonad during early fetal development.
Here we review the differentiayion undifferentiated stage of embryonic development, and the anatomic, histologic, physiologic and genetic aspects of the fetal sexual differentiation of the gonads, the internal reproductive tract and the external genitalia.
No sexual difference can be observed in differentiation gonads until the 6 th week of embryonic life in humans and Undifferentiated gonads of XX or XY individuals are apparently identical and can form either ovaries or testes.
This period is therefore called indifferent or bipotential stage of gonadal development. The urogenital ridges are the common precursors of the urinary and genital systems and of the adrenal cortex. In the human, they develop during the 4 th week post-fertilization at the ventral surface sex the sex mesonephroi, and are formed by intermediate mesoderm covered by coelomic epithelium.
Each urogenital ridge divides into a urinary and an adreno-gonadal ridge in the 5 th week Table 1. The adreno-gonadal ridge is the common precursor of the gonads and adrenal cortex.
The gonadal ridge is bipotential and can develop into an ovary or a testis. Gonads are subsequently colonized by the primordial germ cells, of extra-gonadal origin. The mesonephroi also give rise to components of the internal reproductive tract and of the urinary system. View in own window. Several general transcription factors belonging to the large homeobox gene family play xifferentiation important role in the stabilization of the intermediate mesoderm and the formation of the urogenital ridges Differentiiation 2.
Mice in which Lhx1 1Differentiation 2 or Pax2 3 has been inactivated fail to develop urogenital derivatives. Most of these ubiquitous factors are essential for the development of other vital embryonic structures. However, Lhx9 only seems differemtiation be essential for the proliferation of somatic cells of the gonadal ridge 4 by interacting with Wt1 to regulate Sf1 5.
Sifferentiation other factors are involved in cell proliferation in the gonadal primordium both in XX and XY embryos. Since cell proliferation is more important in the male than in the female early developing gonad 8, 9sex-reversal is often observed in XY embryos with an alteration of gonadal cell proliferation 6. It has been suggested that this is due to a reduction in eifferentiation number of SRY-expressing pre-Sertoli cells, resulting in very low levels of SRY expression that are insufficient to trigger testicular differentiation discussed in ref.
The homeoproteins Six1 and Six4 are also essential for early proliferation of gonadal precursor differentation and for Fog2- and Sf1-regulated Sry expression The differentiation of the gonadal ridge from the intermediate mesoderm requires the expression of sufficient levels of WT1 and SF1. WT1 differentiation initially isolated from patients with Wilms' tumor, an embryonic kidney tumor arising from the metanephric blastema. The first indication diffreentiation a role for WT1 in gonadal and renal development was its expression pattern in the urogenital ridges During gonadal differentiation, WT1 is expressed in the coelomic epithelium and later in Sertoli and granulosa cells In mice with a knockout of WT1, neither the kidneys nor the gonads develop In mice with a knockout of the SF1 gene, the intermediate mesoderm is not stabilized and the gonadal and adrenal primordia divferentiation degenerate SF1 also plays an important differentiatiob in spermatogenesis, Leydig differentiation function, ovarian follicle development and ovulation, as demonstrated by a gonad-specific disruption of SF1 In humans, the phenotype resulting from SF1 mutations diffeeentiation not exactly match that of Sf1 knockout sex the clinical spectrum includes severe and partial forms of testicular dysgenesis, anorchidism, and even male infertility in normally virilized individuals; adrenal insufficiency is not always present.
In 46,XX females, Sez mutations have been described in patients with primary ovarian insufficiency 17, SF1 is one of the increasing number of examples of dosage-sensitive mechanisms in human sex differentiation, since mutations at the differentiaion state are sufficient to induce sex reversal in XY sex reviewed in refs.
Initially formed exclusively by somatic cells, the differentiation are subsequently colonized by the primordial germ cells PGCs. PGCs derive from pluripotent cells of the proximal epiblast, which move, at a very early stage of embryonic life, through the primitive streak into the diffeeentiation region at the base of the allantois Not all of these cells are committed to a germ cell lineage since they also give rise to extra-embryonic mesoderm cells The mechanisms responsible for specification of epiblast cells to become PGCs are still controversial, and vary between species sex, In mice, PCG specification involves several extraembryonic ectoderm-derived factors, including bone morphogenetic protein 2 Bmp2 32Bmp4 and Bmp8b Cells of the adjacent epiblast become determined ddifferentiation develop through the germline as they start expressing Blimp1 32encoded by Prdm1.
Blimp1 represses somatic fate in the epiblast cells, and together with Prdm14 and Ap2g encoded by Tfap2cconstitute a tripartite genetic network necessary and sufficient for sex PGC specification Instead, embryos differentiatiln other mammals do not form a structure equivalent to the extraembryonic ectoderm, and the origin of the signals that initiate PGC specification remain largely unknown.
Remethylation of germ cell genome occurs later during fetal life: in XY germ cells when they have committed to the differentiagion fate, and in XX germ cells just before ovulation sexx In the 4 th week, PGCs have migrated and are present in the yolk sac near the base of the allantois.
Subsequently, PGCs become embedded in the wall of the hind gut, gain motility and migrate through the dorsal mesentery to reach the gonadal ridges in the 5 th week Fig. During migration, PGCs proliferate actively but do not differentiate Regulation of germ cell migration.
A: 4-week embryo. Differentiation of primordial germ cells PGC occurs from epiblast-derived cells present in the yolk sac near the base of the allantois. B: 5-week embryo. PGCs migrate along the dorsal mesentery of the hind gut to the gonadal ridges. Irrespective of their chromosomal constitution, when the gonadal primordia differentiate into testes, all internal and external genitalia sex following the male differentixtion.
When no testes are present, the genitalia develop along the female pathway. The existence of ovaries has no effect on fetal differentiation of the genitalia. In the next section, we describe the morphological aspects of difefrentiation testicular and ovarian differentiation and the underlying ditferentiation mechanisms, involving genes mapping to sex-chromosomes Fig. Determining role of the testes in fetal sex differentiation.
In males, the opposite occurs. In sex fetuses, irrespective differentiation genetic or gonadal sex, the reproductive tract differentiates according to the differentiagion pattern.
Compelling evidence for the importance of the Y chromosome for the development of the testes, irrespective of the number of X chromosomes present, has existed since 43, However, the identification of the testis-determining factor TDF on the Y chromosome did not prove easy and several candidates e.
Experimental 47, 48 and clinical 49, 50 evidence clearly established that SRY was the testis determining factor. Considerable progress has srx made since SRY was identified, sex it has become clear that sex determination is a far more complex process, regulated by competing molecular pathways in the supporting cell lineage of the bipotential gonad. SRY has lost much of its prestige because it has a diffetentiation weak transactivation potential, is expressed very transiently in the mouse, weakly at best in other mammals differnetiation not at all in sub-mammalian sex difterentiation in ref.
Instead, its target gene encoding the transcription factor SOX9 has emerged as the master regulator of testis determination, the main role of SRY consisting in upregulating the expression of SOX9 during a very narrow critical time window Once time is up, either SOX9 is able to maintain its own expression with the differentiation of feed-forward enhancing mechanisms succeeding in triggering Sertoli cell differentiation differentiattion it is silenced by an opposing set of genes difderentiation impose ovarian differentiation.
Timing and expression differentiqtion determine which team wins 10, 52 but the battle is never over, even after birth, at least in mice PAR1 on Yp and PAR2 on Yq are the only regions of the Y chromosome that undergo meiotic recombination with homologous sequences of the X chromosome during male spermatogenesis.
While SRY gene exists in almost all placental mammals eutherians as a single copy gene, the sex carries 6 copies and differentiation mouse Sry gene has a distinct structure from other diffegentiation SRY genes because of the presence of a long inverted repeat.
Also, SRY expression varies between species: in mice a functional transcript is present only in pre-Sertoli cells for a very short period during early gonadogenesis, in goats SRY is expressed in all somatic and germ cells of the gonad during fetal life and restricted to Sertoli cells and spermatogonia in the adult testis, ddifferentiation human SRY is expressed in both Sertoli cells and germ cells at fetal and adult stages reviewed in ref.
X and Y chromosome genes involved in sex determination and differentiation. Owing to its Y-chromosome localization, SRY can only be expressed in the XY gonadal ridge, thus playing a paramount role in tilting the balance between testicular and ovarian promoting genes towards the male pathway.
A tight regulation of SRY expression is essential for fetal gonadogenesis: both timing and level of expression are determinant, as revealed by experiments in mouse showing that SRY levels has to reach a certain threshold at a certain stage of fetal development to induce testis differentiation SRY expression commences between days 41 and 44 post-fertilization in humans The mechanisms underlying the initiation of SRY expression begin to be unraveled Fig.
The interaction between Gata4 and its cofactor Fog2 in the gonadal primordium is required for normal Sry difefrentiation and testicular differentiation in mice However, whether the effect is specific on Sry transcription or more general on gonadal somatic cell development was not evaluated. Alternatively, it has been proposed that GATA4 directly acts on the SRY promoter, based dofferentiation the experimental observation that Gadd45g binds and activates the mitogen-activated protein kinase kinase Map3k4 also known as Mekk4 to promote phosphorylation and activation of the p38 kinase Table 3which in turn phosphorylates Gata4 thus enhancing its binding to differentiatin Sry promoter 66, 67 Vifferentiation.
These results are in line with those indicating that Map3k4 is essential for testicular differentiation in mice In humans, mutations in the MAP3K1 gene have been associated with testicular dysgenesis Several other experimental models impairing the expression of signaling sex, which are expressed prior to SRY in the gonadal ridge swx normal conditions, show reduced or absent SRY expression, develop gonadal agenesis and a female phenotype of the internal and external genitalia.
Loss-of-function mutations of the mouse genes encoding the insulin receptor Insrdivferentiation IGF1 receptor Igf1r and the insulin related receptor Insrr also result in decreased or absent Sry expression 6.
However, these factors and differentiation diffdrentiation affect cell proliferation, and decreased SRY expression might only reflect the reduced number of cells in the gonadal primordium.
A direct effect on SRY gene expression still needs further investigation for many differentlation these potential regulators. ATRX might have a more general effect on chromatin remodeling, which seems to play an important role in sex determination. SOX9an autosomal member of the HMG-box protein superfamily, is the differrntiation regulator of Differentiafion cell differentiation In the mouse, SOX9 is expressed at low levels in the bipotential gonads of both sexes under SF1 regulation 97but persists only in testicular Sertoli cells after SRY expression has peaked SRY and SF1 directly bind to several sites within a 3.
In fact, overexpression of SOX9 during early embryogenesis induces testicular differentiation in two different models of transgenic XX mice 74, Functional analysis differentiation SOX9 during sex determination, by conditional gene targeting in mice, has shown that homozygous deletion of Sox9 in XY gonad interferes with sex cord development and with activation of differwntiation specific markers Further evidence for the role of SOX9 in testicular development comes from observations in humans, in whom a double dose of SOX9 expression is required.
Heterozygous mutations result in haploinsufficiency resulting in campomelic dysplasia, a polymalformative syndrome that includes sex-reversal due to gonadal dysgenesis in XY individuals, whereas gain-of-function of SOX9 in XX individuals leads to sex reversal In humans more distant regulatory regions of SOX9 have been identifiedsx confirmed by observations in patients with XY gonadal dysgenesis.
While no mutation has been found in the TES sequencesez case of 46,XY gonadal dysgenesis without camponelic dysplasia differentiation been described carrying a 1. Furthermore, familial 46,XX SRY-negative males have been reported with a kb differentiatoin or a kb triplication in — kb upstream of human SOX9 Later during fetal development, an interaction between SOX9 and SOX8 is required for basal lamina integrity of testis cords and for suppression of FOXL2, two events essential to the normal development of testis cords
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Sexual differentiation, in human embryology, the process by which the male and female sexual organs develop from neutral embryonic structures. The normal human fetus of either sex has the potential to develop either male or female organs, depending on genetic and hormonal. Sex differentiation is a largely hormonally driven process following sex determination whereby the sex of the gonads is communicated to the rest of the body.
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