Chromosomal Sex Determination
NCBI Bookshelf. Primary sex determination is the determination of the gonads. In mammals, primary sex determination is ppt chromosomal and is not usually influenced by the environment.
In most cases, the female is XX determination the male is XY. Every individual must have at least one X chromosome. Since the female is XX, each of her eggs has a single X chromosome. The male, being XY, can generate two types of sperm: half bear the X chromosome, half the Y.
If the egg receives another X chromosome from the sperm, the resulting individual sex XX, forms ovaries, and is female; if the egg receives a Y chromosome from the sperm, the individual is XY, forms testes, and is male. The Y chromosome carries a gene that encodes a testis-determining factor. This factor organizes the gonad into ppt testis rather than an ovary. Unlike the situation in Drosophila discussed belowthe mammalian Y chromosome is a crucial factor for determining sex in mammals.
Furthermore, an individual with only a single X chromosome and no ppt X or Determination i. For a complete ovary, a second X chromosome is needed. Moreover, as we shall see, both diverge from a common precursor, the bipotential gonad.
Secondary sex determination affects the bodily determination outside the gonads. Humans male mammal has a penis, seminal vesicles, and prostate gland. A female mammal has a vagina, cervix, uterus, oviducts, and mammary glands. In many species, each sex has a sex-specific size, vocal cartilage, and musculature. These secondary sex characteristics are usually determined by hormones secreted from the gonads. However, in the absence of gonads, the female phenotype is generated.
When Jost removed fetal rabbit gonads before they had differentiated, the resulting rabbits had a female phenotype, regardless of whether they were XX or XY. They each had oviducts, a uterus, and a vagina, and each lacked a penis and male accessory structures. The general scheme of mammalian sex determination is shown in Figure If the Y chromosome is absent, the gonadal primordia develop into ovaries.
If the Y chromosome is present, testes form and secrete two major hormones. The second hormone— testosterone —masculinizes the fetus, stimulating the formation of the penis, scrotum, and other portions of the male anatomy, as well as inhibiting the development of the breast primordia.
Thus, the body has the female phenotype unless it is changed by the two hormones secreted by the fetal testes. We will now take a more ppt look at these events. Sex cascades leading to the formation of the sexual phenotypes in mammals.
The conversion of the genital ridge into the bipotential gonad requires the LHX9, SF1 and WT1 genes, since mice lacking either of these genes humans gonads. The bipotential more The gonads embody a unique embryological situation.
All other organ determination can normally differentiate into only one type of organ. A lung rudiment can become only a lung, and a liver rudiment can humans only into a liver. The gonadal rudiment, however, has two sex options. When it differentiates, it can develop into either an ovary or a testis.
The path of sex taken by this rudiment determines the future sexual development of the organism. But, before this decision is made, the mammalian gonad first develops through a bipotential indifferent stageduring which time sex has neither female nor male characteristics.
In humans, the gonadal rudiments appear in the intermediate mesoderm during week 4 and remains sexually indifferent until week 7. The gonadal rudiments are paired regions of the intermediate mesoderm; they form adjacent to the developing kidneys. The ventral portions of the gonadal rudiments are composed of the genital ridge epithelium.
During the indifferent stage, the genital ridge epithelium proliferates into the loose connective humans tissue above it Figure These epithelial layers form the sex cords.
The germ cells migrate into the gonad during week 6, and are surrounded by the sex cords. In both XY and XX gonads, the sex cords remain connected to the surface epithelium. Differentiation of human gonads shown in transverse section. A Genital ridge of a 4-week embryo. Sex Genital ridge of a 6-week indifferent gonad showing primitive sex cords.
C Testis development in the eighth week. The sex cords lose contact with more If the fetus is XY, ppt sex cords continue to proliferate through the eighth week, extending deeply into the connective tissue. These cords fuse, forming a network of internal medullary sex cords and, at its most distal end, the thinner rete testis Figure Eventually, the sex ppt called testis cords —lose contact with the surface epithelium and become separated from it by a thick extracellular matrix, the sex albuginea.
Thus, the germ cells are found in the cords within the testes. During fetal life and childhood, the testis cords remain solid. At puberty, however, the cords will hollow out to form the seminiferous tubulesand the germ cells will begin to differentiate into sperm. The cells of the seminiferous tubule are called Sertoli cells. The sex are transported from the inside of the testis through the rete testis, which joins the efferent ducts. These efferent tubules are the remnants of the mesonephric kidney, and they link the testis to the Wolffian duct, which used to be the collecting tube of the mesonephric kidney see Chapter In males, the Wolffian duct differentiates to become the epididymis adjacent to the testis and the vas deferensthe tube through which the sperm pass into the urethra and out of the body.
Meanwhile, during fetal ppt, the interstitial mesenchyme cells of the testes differentiate into Leydig cellswhich make testosterone. Mammalian gonads. The histology of the mammalian ovary and testis can be seen in sex photographs that show progressively smaller regions at higher magnifications. In females, the germ cells will reside near the ppt surface of the gonad. Unlike the sex cords in males, which continue their proliferation, the initial sex cords of XX gonads degenerate.
However, the epithelium soon produces a new set of sex cords, which do not penetrate deeply into the mesenchyme, but stay near the humans surface cortex of the organ. Thus, they are called cortical sex cords. These cords are split into clusters, with each cluster surrounding a germ cell Figure The germ cells will become the ova, and the surrounding cortical sex cords will differentiate into the granulosa cells.
The mesenchyme cells of the ovary differentiate into the thecal cells. Humans, the thecal and granulosa cells will form the follicles that envelop determination germ cells and secrete steroid hormones. Each follicle will contain a single germ cell.
The Wolffian duct, determination of testosterone, degenerates. A summary of the development of mammalian reproductive systems ppt shown in Figure Summary of the development of the gonads and ppt ducts in mammals. Several genes have been found whose function is necessary for normal sexual differentiation. Unlike those that act in other developing organs, the genes involved in sex determination differ extensively between phyla, so one cannot look at Drosophila sex-determining genes sex expect to see their homologues directing mammalian sex determination.
However, since the phenotype of mutations in sex-determining genes is often sterility, determination studies have been used to identify those genes that are active in determining determination humans become male or female. Experimental manipulations to confirm the functions of these genes can be done in mice. In humans, the major gene for the sex factor resides on the short arm of the Y chromosome.
Individuals who are born with the short arm but not the long arm of the Y chromosome are male, while individuals born with the long arm of the Y chromosome but not the short arm are female. By analyzing the DNA of rare XX men and XY women, the position of the testis-determining gene has been narrowed down to a 35,base-pair region of the Y humans located near the tip of the short arm. In this region, Sinclair and colleagues found ppt male-specific DNA sequence that could encode a peptide of amino acids.
This peptide is probably a transcription factor, since it contains a DNA-binding domain called the Determination h igh- m obility g roup box.
This humans is found in humans transcription factors and nonhistone chromatin proteins, and it induces bending in the region of DNA to which it binds Figure This gene is called SRY s ex-determining r egion of the Y pptand there is extensive evidence that it is determination the gene that encodes sex human testis-determining factor. It is thought that several testis-specific genes contain SRY-binding sites in their promoters or enhancers, and that the binding of SRY to these sites begins the developmental pathway to testis formation Cohen et al.
After Haqq et al. If SRY actually does encode the major testis-determining factor, one would expect that it would act in the genital ridge immediately determination or during testis differentiation. This prediction has been met in studies of the homologous gene found in mice.
The mouse humans Sry also correlates with the presence of testes; it is present in XX males and humans in XY females Gubbay et al. The Sry gene is expressed in the somatic cells of the bipotential mouse gonad immediately before or during its differentiating into a testis; its expression then disappears Hacker et al.
The most impressive evidence for Sry being the gene for testis-determining factor comes from transgenic mice. Koopman and colleagues took the kilobase determination of DNA that includes the Sry gene and presumably its regulatory elements and microinjected this sequence into the pronuclei of newly fertilized mouse zygotes.
In several instances, the XX embryos injected with this sequence developed testes, male accessory organs, and penises Figure Functional sperm were not formed, but they were not expected, either, because the presence of two X chromosomes prevents sperm formation in XXY mice and men, and the humans mice lacked the rest of the Y chromosome, which contains genes needed for spermatogenesis.
An XX mouse transgenic for Sry is male. A Polymerase chain reaction followed by electrophoresis shows the presence of the Sry gene in normal XY males and in a transgenic XX Sry mouse.
The gene is absent in a female XX littermate.
Primary and secondary sex determination
Our knowledge of mammalian sex determination is based on two main areas of study. First, the characterization of the biological events that determine the sexual ppt of the individual, including patterns of gene expression, and second, the study of genetic mutations in humans and mice that lead to abnormal sexual phenotypes. In the search for molecular components of this process, the sex of genes in loci involved in human disease has been especially fruitful.
Serendipity has also played a hand, where in several cases targeted mutations in mouse genes, being studied for other reasons, have led to unexpected humans reversal phenotypes. The collection of molecular candidates implicated in sex determination is now quite extensive. We are not able to fit ppt of these into simple pathways, where one gene acts on the next and so on in a linear fashion, as seems possible in the sex model organisms, Caenorhabditis elegans and Drosophila. In determination this is due to gaps in our knowledge, as we are clearly missing several key components, but sex is looking increasingly likely that the system is much better described as a network of factors.
In fact, ppt story so far is like some partly recovered script for a play. Thus some gene products are main characters with roles at several different stages, some act as a chorus, in a combinatorial fashion with others, whereas a few play a critical role in one scene and then disappear. The mechanism presumably evolved to be delicately poised to respond to the initial trigger to be male or female and then to amplify this decision while avoiding development of determination phenotypes.
It is therefore likely to be a system full sex back-ups and functional redundancy. The complexity may also follow from the relatively late embryonic stage at humans the decision is reached. This means that events occurring in one cell lineage have to be coordinated with others in the context of a developing organ and eventually the whole organism.
We review here the story that is beginning to emerge, focusing mostly on the determination of transcription factors that appear to play important leading and supporting roles. In mammals, the genetic sex of the embryo is established at fertilization with the inheritance of an X or Y chromosome from the father.
However, the sex-determining process is set in motion only during the period of organogenesis when the gonads develop. The Y chromosome, ppt the determination gene Sryacts dominantly to trigger sex of testes from the indifferent gonads or genital ridges that would otherwise develop as ovaries Gubbay et al.
Humans is the only gene needed from the Y chromosome to establish male development, as shown by transgenic experiments where XX mice carrying the Sry gene develop as males Koopman et al. Conversely, mutations in Sry can lead to relatively normal female development of XY mice and humans Gubbay et al. Once the humans begin to differentiate as testes or ovaries, they secrete factors, notably anti-Mullerian hormone AMH, otherwise known as Mullerian-inhibiting substance, or MIS and testosterone from the testes, which determination the sexual development of the rest of the embryo.
There are many steps in this process that, when affected, will give rise to different degrees of sex reversal. The challenge has been to correlate the phenotype of affected individuals with humans appropriate step and translate this into a molecular mechanism.
The mammalian gonad forms within the developing urogenital system, which itself derives from the intermediate mesoderm that runs the length of the embryo on either side of the midline axial and paraxial structures.
This system is divided into three regions: pronephros, mesonephros, and metanephros, which develop anterior to posterior along the nephric or Wolffian duct Fig. The pronephros is vestigial in mammals but the mesonephros can serve as a primitive kidney during embryogenesis in some species. The definitive kidney is the product of the interaction between the metanephric mesenchyme at the posterior end of the urogenital system and the ureteric bud, which grows out of the Wolffian ppt.
A second duct, the paramesonephric or Mullerian duct, originates within each mesonephros by invagination of the coelomic epithelium. This duct runs parallel to the Wolffian duct but turns toward the midline at the posterior end of the mesonephros and fuses with the companion duct.
The genital ridges are composed of somatic cells derived from the mesonephros and primordial germ cells that have migrated, via the hindgut and mesonephros, from extraembryonic mesoderm at the base of the allantois Ginsburg et al.
Mutation studies have identified several genes essential for early gonad development. The role of these in sex determination, however, is not always clear. The consequences of the mutations are often too severe to address whether the products of these genes are involved in upstream events, such as Sry regulation, whether they act as partner factors, or whether they have critical humans downstream determination the control of sex-specific gene regulation.
Indeed, they could act at all these levels. One such gene encodes steroidogenic factor 1 SF1 Lala et al. SF1 is a member of the subfamily of nuclear receptors, the orphan receptors, for which no clear activating ligand has been found.
This ppt factor has a DNA-binding humans composed of two zinc fingers, ppt are highly conserved among mammals. Also conserved is a domain at the carboxyl terminal of the zinc finger region, which is similar to that found in a subset of nuclear receptors that interact as monomers with an AGGTCA motif in the DNA. SF1 was first identified as an activator of genes involved in steroid biosynthesis in different steroid hormone producing cells Humans et al. Expression studies in mice showed that SF1 is present during embryo development in regions associated with endocrine function such as gonads, adrenals, pituitary, and hypothalamus Hatano et al.
Mice with a homozygous disruption of the Sf1 gene lack gonads and adrenals and have impaired gonadotrope function and ventromedial hypothalamic structure Ingraham et al. These studies show that this factor has an essential role as a regulator of endocrine differentiation at multiple levels. The gonads of embryos lacking Sf1 cease to develop between 11— The adrenal glands also fail to form. However, the essential role of SF1 in the development of determination these organs remains unclear.
The genital ridges begin to form and are colonized by the germ cells, which must still receive the correct signals to direct their migration. SF1 is therefore not involved in specifying the initial development of the gonad along the urogenital system, or the acquisition of early gonadal cell identity.
Sf1 gene expression is specifically associated with the gonad and the adrenal as they arise and is a good marker of these cells. Careful expression studies in the rat using an antibody to SF1 have shown a population of positive cells present just before the gonad can be observed morphologically. This group of cells will later separate humans form the somatic cells of the gonad and the cortical cells of the adrenal Hatano et al. This is in agreement with the proposal that these two organs are derived from the same primordia.
The origin of these adrenogenital cells is still not well ppt but they could be derived from coelomic epithelia, mesonephric mesenchyme, or mesonephric ducts Fig. Advances are being made with studies in which immature gonadal cells are labeled with lineage tracers and the fate of these cells is followed after development of the gonad in vitro. These studies show that the coelomic epithelium, which lines the coelomic cavity, contributes to somatic cells of the gonad, including Sertoli cells Karl and Capel Further studies will define if the underlying mesenchyme or the ducts also contribute sex the determination of the early gonad, although the Pax2 mutant phenotype see below suggests that the ducts are not necessary.
Structure of sex urogenital system. Schematic of the mouse urogenital system at Epithelial structures are shown in red, mesenchymal structures are shown in blue, and the striped region denotes the genital ridge. Genes that are important in the differentiation of the intermediate mesoderm and the urogenital system as a whole will generally have a role in early gonad development.
This group of genes is characterized by their mutant phenotypes, which show defects in both sex kidney and gonad development.
Lim1which encodes a member of the LIM class of homeobox proteins, is one such gene. Mice homozygous for deletions in Lim1 have no kidneys or gonads Shawlot and Behringer The gene is expressed during early urogenital development in the mesonephric duct and tubules and in the ureteric bud in the metanephros Fujii et al. Interestingly, PAX2, ppt member of the paired-box family of transcription factors, is found in much the same regions although it is also found in the mesenchyme.
However, whereas the Pax2 -deficient mice lack kidneys and urogenital ducts, the gonads and adrenals do form Torres et al.
Both Lim1 and Pax2 are thought to have essential functions during the very early phases of kidney development Vainio and Mullerbut the ppt of Lim1 in early gonad development has not been studied in any detail. Humans gene is complex as it encodes a variety of protein products with different functions.
The WT1 gene in mouse and man is comprised of 10 exons and there are four major species of RNA generated by two different alternative splicing events Reddy and Lichtand references therein.
In addition, there are two alternative translation start points and sex RNA editing leads to isoforms that differ in one residue Sharma et al. There are, therefore, 16 possible forms of the protein. Overall there are several functional domains within the protein Fig.
The domain at the carboxyl terminus contains four DNA-binding zinc fingers homologous to those of the early growth response family of transcription factors EGR. Isoforms that are otherwise identical, but for the presence or absence, through alternative splicing, of three amino acids lysine, determination, and serine, Determination between the third and fourth zinc fingers, have different affinity for DNA.
A transregulatory domain, which is proline and glutamine rich, has been mapped to the amino terminus. This suggests that WT1 can act as a transcription factor. Studies performed in vitro with some forms of WT1 show that it can regulate sex in different ways.
In certain contexts it binds DNA and can act as either a repressor or an activator; in others it may work as a coactivator where DNA binding is not required Reddy and Lichtand references therein; Nachtigal et al. It appears therefore that WT1 can regulate cell function at several different levels. Protein structure. Shown are the structural domains found in several proteins involved in sex determination. In the case of Sry, the structure of the mouse m and human h proteins are shown. WT1 mutations are involved in three different but related syndromes in humans.
Heterozygous deletions of the gene are associated with mild genitourinary malformations and will predispose to childhood kidney tumors. In Denys—Drash syndrome, heterozygous missense mutations in the zinc finger DNA-binding domain of WT1 lead to severe and more frequent urogenital malformations Pelletier et al.
It is thought that these mutant forms of the protein sex as dominant negatives that cannot bind DNA and interfere with wild-type WT1 action. XY individuals with Denys—Drash syndrome are more affected than XX and sometimes show ambiguous or female genitalia, suggesting that the gene is involved in male urogenital development. Consistent with this, XY patients with Frasier syndrome develop as females and display urogenital malformations.
This may indicate a critical RNA determination function for the protein in sex determination. In contrast to humans, mice carrying a heterozygous deletion in the Wt1 gene do not develop tumors or have genitourinary malformations.
Homozygous deletions of Wt1however, lead to an absence of gonads and arrested kidney development Kreidberg et al. During embryogenesis, the Wt1 gene is expressed throughout the intermediate mesoderm at 9.
In the kidney, WT1 is required for ureteric growth although it is not expressed in the ureteric bud but in the metanephric mesenchyme Pritchard-Jones et al. Recent studies have shown that WT1 is also important for the formation of most mesonephric tubules that depend on a mesenchyme to epithelial transition Sainio et al.
Inductive events between mesenchyme and epithelia have not been well characterized in the developing gonad, however, it may be that WT1 similarly regulates inductive signals from the mesenchyme to the coelomic epithelia in this organ. If so, it may be responsible for the growth of the genital ridge by directing the ingression of cells from the coelomic epithelium.
As these cells contribute to Sertoli cells Karl and Capelmutations in Wt1 could lead to sex reversal simply because of a deficiency humans their precursors. Mice deficient for the gene encoding EMX2, a transcription factor containing a homeobox domain, also show impaired gonadal and kidney development Miyamoto et al.
At The analysis of the kidney defect ppt that EMX2 is necessary for the response of the ureteric bud to the signal from the mesenchyme. This would place this gene downstream of WT1 in the cascade of kidney development.
Developmental Biology. 6th edition.
It appears therefore that WT1 can regulate cell function at several different levels. Protein structure. Shown are the structural domains found in several proteins involved in sex determination. In the case of Sry, the structure of the mouse m and human h proteins are shown. WT1 mutations are involved in three different but related syndromes in humans. Heterozygous deletions of the gene are associated with mild genitourinary malformations and will predispose to childhood kidney tumors.
In Denys—Drash syndrome, heterozygous missense mutations in the zinc finger DNA-binding domain of WT1 lead to severe and more frequent urogenital malformations Pelletier et al. It is thought that these mutant forms of the protein act as dominant negatives that cannot bind DNA and interfere with wild-type WT1 action.
XY individuals with Denys—Drash syndrome are more affected than XX and sometimes show ambiguous or female genitalia, suggesting that the gene is involved in male urogenital development. Consistent with this, XY patients with Frasier syndrome develop as females and display urogenital malformations. This may indicate a critical RNA processing function for the protein in sex determination. In contrast to humans, mice carrying a heterozygous deletion in the Wt1 gene do not develop tumors or have genitourinary malformations.
Homozygous deletions of Wt1 , however, lead to an absence of gonads and arrested kidney development Kreidberg et al. During embryogenesis, the Wt1 gene is expressed throughout the intermediate mesoderm at 9.
In the kidney, WT1 is required for ureteric growth although it is not expressed in the ureteric bud but in the metanephric mesenchyme Pritchard-Jones et al. Recent studies have shown that WT1 is also important for the formation of most mesonephric tubules that depend on a mesenchyme to epithelial transition Sainio et al.
Inductive events between mesenchyme and epithelia have not been well characterized in the developing gonad, however, it may be that WT1 similarly regulates inductive signals from the mesenchyme to the coelomic epithelia in this organ.
If so, it may be responsible for the growth of the genital ridge by directing the ingression of cells from the coelomic epithelium. As these cells contribute to Sertoli cells Karl and Capel , mutations in Wt1 could lead to sex reversal simply because of a deficiency of their precursors. Mice deficient for the gene encoding EMX2, a transcription factor containing a homeobox domain, also show impaired gonadal and kidney development Miyamoto et al.
At The analysis of the kidney defect suggests that EMX2 is necessary for the response of the ureteric bud to the signal from the mesenchyme. This would place this gene downstream of WT1 in the cascade of kidney development. Consistent with this, Wt1 expression is unaffected in the Emx2 mutants.
However, the role of Emx2 in gonad development is still not clear. Emx2 is expressed in the genital ridge as well as the Wolffian duct, mesonephric tubule, and coelomic epithelia. Interestingly, the Emx2 -deficient mice show normal adrenal development. This would suggest that the gonadal defect in these mice can not be due to a failure in the SF1 positive cells of the gonad, which are shared with the adrenal.
Perhaps Emx2 is required to sustain the coleomic epithelium and gonadal development is more sensitive to the state of the epithelium than the adrenals.
A recent report on the mouse M33 gene, which is related to the Drosophila polycomb group PcG genes, has suggested that it is involved in the early development of the gonad but in a different way to the factors mentioned above. Mice carrying a disrupted M33 gene show retarded gonad development Katoh-Fukui et al. Unlike the case for disruptions in the genes described above, these retarded gonads do give rise to adult organs although they are not completely normal and the phenotype is variable.
The XY animals showed different degrees of sex reversal. It is not clear what stage of testis development is affected in the Mmutant mice. Analysis of early testicular markers in these mice will establish whether this gene acts upstream or downstream of Sry. The PcG proteins in Drosophila are thought to be part of a system that maintains the pattern of expression of homeotic genes, which are responsible for providing positional information to the embryo.
The role of polycomb proteins is to repress gene expression by forming a multimeric complex that compacts chromatin making it inaccessible to transcription factors. Loss-of-function mutations in polycomb lead to posterior homeotic transformations. Consistent with this, the M33 -deficient mice do show homeotic transformations in the structure of their skeleton Core et al.
It is possible that these mice also have a defect in positional information during gonad development. The cells of the mesonephros without M33 may have acquired partial metanephric identity and therefore gonad development is affected. Alternatively, there may be a defect in the timing of the development of the gonad with respect to the timing of the differentiation of the rest of the urogenital system. The homeotic gene targets for M33 in the urogenital system are not known, but different Hox genes are expressed along the urogenital system Dolle et al.
There are essentially three different cell lineages present in the gonad as well as the germ cells. Each lineage has a bipotential fate depending on the sex of the organ in which they are found. The supporting cell lineage will give rise to Sertoli cells in the testis and follicle cells in the ovary.
These cells surround the germ cells and provide an appropriate growth environment. The steroidogenic cell lineage produces the sexual hormones that will contribute to the development of the secondary sexual characteristics of the embryo.
In the male these are the Leydig cells and in the female, the theca cells. The connective cell lineage will contribute to the formation of the organ as a whole. Early testis development is characterized by the formation of testicular cords that contain Sertoli and germ cells, with the Leydig cells excluded to the interstitium.
The connective cell lineage is a major contributor to cord formation as the peritubular myoid cells surround the Sertoli cells and together they lay down basal lamina. The testis is also characterized by rapid and prominent vascularization. Organization of the ovary takes places later than that of the testis and is less structured, with the connective tissue lineage giving rise to stromal cells and with no myoid cell equivalent Fig.
Morphological changes in the gonad during differentiation. Shown are the molecular and structural changes that occur during differentiation of the mouse gonad along the male top and the female bottom pathway.
The stages of embryo development that are depicted are indicated at the bottom. The genital ridge is shown as a striped structure; the mesonephros is shown in blue. Before After the action of SRY, molecular differences in the gonad can be observed, as depicted at Morphological differences between the testis and the ovary can be observed at The structure of testicular cords, which is a consequence of migration of mesonephric cells, is shown as part of the male pathway.
The different cell types of the testis and ovary are indicated, as are the genes expressed therein. Myoid cells, indicated in blue, are thought to derive from the mesonephric contribution. The different fate of germ cells between the testis and the ovary is shown.
In the mouse, Sry is expressed in the genital ridge as a wave from anterior to posterior that lasts about a day and a half so that each cell sees it for a few hours only Hacker et al. Studies on chimeric mice derived from XX and XY cells showed that almost all of the Sertoli cells in the testes were XY whereas other lineages showed no chromosomal bias Palmer and Burgoyne The action of SRY is therefore thought to trigger differentiation of the Sertoli cell lineage in the testis.
Once SRY triggers Sertoli cells they in turn direct the differentiation of the rest of the cell types in the testis.
Therefore the decision of sex determination is essentially one of cell fate: SRY triggers Sertoli cell fate in a cell that would otherwise become a follicle cell. The switch in cell fate brought about by SRY is likely to occur at the level of transcriptional control. For SRY, this appears to be the most critical part of the protein. With one exception, all mutations found in SRY , in cases of human XY female sex reversal, cluster in this region Harley et al. In addition, the HMG box domain is relatively well conserved, unlike the rest of the protein which is so dissimilar between all but closely related species that it is often impossible to even align Tucker and Lundrigan ; Whitfield et al.
Moreover, binding affinity and the angle of the bend can be affected independently by sex reversing mutations in the box Pontiggia et al. This suggests that an important molecular mechanism underlying SRY action is to change the chromatin configuration and therefore affect transcription by influencing neighboring interactions between DNA and proteins.
The transient nature of Sry expression in the gonad suggests that it acts as a switch toward Sertoli cell fate but that it is not involved in the maintenance of cell identity or cell function.
Therefore, SRY must in some way activate other genes that are involved in defining and maintaining Sertoli cell identity. A candidate for this type of downstream gene is Sox9. However, it also has a strong transactivation domain at its carboxy terminus Sudbeck et al. In addition, the entire protein is highly conserved throughout vertebrate evolution, unlike SRY, which is mammal specific.
Expression studies in the mouse have shown that Sox9 is present at low levels in both male and female genital ridges when the gonad first develops. However, by By This pattern of expression is consistent with the upregulation of Sox9 being a direct effect of SRY action.
It also suggests that it is involved in determining Sertoli cell fate. Significantly, XY human individuals with mutations in one allele of SOX9 , frequently show male to female sex reversal Foster et al. The mutations are found in different regions of the protein implicating several domains, including the HMG box and transcriptional activation domain, in its function in sexual development Kwok et al.
The mutations are also consistent with haploinsufficiency for SOX9 being responsible for the phenotype; that is, the protein has to reach above a criticical threshold to be effective. The close association of Sox9 expression with Sertoli cell fate and the consequences of mutations in the human gene argue that Sox9 is essential for early testis development. Other vertebrates, even if they lack the Sry gene, show conserved expression patterns of Sox9 in the ovary and testis.
Chicken and turtle Sox9 gene expression is associated with the developing testis but not with the ovary Kent et al. These studies suggest that Sox9 is important in testis development in many species and that it is the common direct downstream gene of different sex determining mechanisms.
The studies described above are consistent with the model that one of the main roles of SRY is to upregulate Sox9 expression in Sertoli cell precursors. The molecular mechanism of SRY action has yet to be determined, but there are a few candidate genes thought to be part of this mechanism. The best described of these is Dax1 , an X-linked member of the nuclear hormone receptor NHR superfamily.
Studies in the mouse have shown that Dax1 is expressed in the genital ridge at the same time as Sry but in both sexes Swain et al. As differentiation proceeds Dax1 is down-regulated in the testis but stays on in the ovary Fig. Genetic data have provided proof that Dax1 is part of the sex-determination mechanism, but that it is not required for testis formation.
That DAX1 is the gene responsible for the latter was shown in transgenic mouse experiments, where overexpression of Dax1 alone was able to give XY female sex reversal in certain genetic backgrounds Swain et al.
Expression pattern in the gonad during development. Shown are the expression patterns of genes involved in sex determination in the male and female gonad at different stages of embryonic development. The pattern of expression depicted is representative of the gonad as a whole up to 12 dpc, which includes precursors to supporting cells Sertoli cells in the male and follicle cells in the female and possibly steroidogenic cells Leydig cells in the male and theca cells in the female.
After 12 dpc, the pattern depicted is representative of supporting cells in both sexes. Expression of GATA4 in the early stages of genital ridge development is not known. DAX1 is also thought to act in the same pathway as SF1. Their patterns of expression correlate quite closely and include the gonad, adrenal, hypothalamus, and pituitary, implicating both these genes in reproductive function Ikeda et al.
The phenotypes though related are not the same indicating a complex interaction between these two genes. The most striking difference between the phenotypes is in the gonad. DAX1 is an unusual member of the nuclear hormone receptor family in that it does not possess a classical zinc finger-containing DNA-binding domain, but three-and-a-half copies of a amino acid repeated motif linked to the ligand-binding domain. Studies from different laboratories have shown that DAX1 can inhibit the transcriptional activation of SF1 in vitro Ito et al.
SF1 is a known activator of genes involved in steroid biosynthesis and in vitro studies have shown that it interacts with a coactivating complex in a similar way to other nuclear hormone receptors Ito et al. It has been proposed that the mechanism of repression by DAX1 involves direct protein-protein interaction with SF1, and either direct repression of transcription or recruitment by DAX1 of the nuclear receptor corepressor, N-COR, a known silencer of nuclear hormone receptor mediated transcription.
These inhibitory properties have been mapped to the carboxyl terminus of DAX1 and importantly this region is deleted from all naturally occurring deletion mutations in humans Fig. However, more recently, Zazopoulos et al. These are predicted to form when unique sequences are flanked by inverted repeats, and Zazopoulos et al.
Clearly, architectural factors such as SRY could influence the likelihood of hairpin—loop structures forming, which immediately suggests a mechanism by which SRY and DAX1 could act antagonistically to control the activity of SF1 on one or more critical target genes involved in sex determination. However, there is no evidence for this at present.
Dax1 and SF1 are coexpressed in the adrenal and deficiencies in both these genes lead to impaired adrenal development. The phenotypes are different, however, in that Sf1 -deficient mice lack adrenals altogether, whereas humans with a deletion of the DAX1 gene show absence of the adult zone of the adrenal cortex.
Recent studies have shown that mice with a deletion of the carboxy-terminal portion of the ligand-binding domain of DAX1 also show abnormal development of the adrenal in that the fetal zone of the cortex does not regress Yu et al. In contrast to humans, however, the adult zone is normal and the mutant animals do not suffer adrenal failure. It is possible that the phenotype seen in the DAX1 -deficient patients is due to an excess of SF1 function, which might affect mice differently.
Detailed analysis of adrenals from mice deficient for Dax1 will address this issue. The action of DAX1 on SF1 could also be affected by the presence of a ligand for both or either of these orphan receptors. The sequence of the SF1 and DAX1 ligand-binding domains suggests they can interact with a ligand and this idea is supported by in vitro studies where deletions of the SF1 ligand binding domain lead to an increase in SF1-mediated transactivation of Amh-reporter constructs Shen et al.
Attempts to find ligands that may operate in vivo have so far given equivocal results. It remains to be established whether SF1 has a critical role in sex determination per se, that is, the decision to be testis rather than ovary, in addition to being generally required for gonadal development.
The expression of Sf1 is identical in XX and XY genital ridges up to the stages when Sry is expressed in the male, but subsequently, higher levels of Sf1 are associated with the testis. Some of this is due to the differentiation of Leydig cells, where SF1 is clearly required for steroidogenesis, but Sertoli cells also appear to have higher levels of Sf1 than follicle cells Shen et al.
SF1 could therefore participate in the determination and differentiation of Sertoli cells, first by being an upstream regulator of either Sry or Sox9 or both, but secondly by being downstream of these. Perhaps SF1 and SOX9 are mutually dependent on each other for their continued expression at a high level. SF1 could then participate in subsequent Sertoli cell-specific gene regulation.
The pattern of expression of SF1 is complementary to that of DAX1 in the gonad and suggests that these receptors act antagonistically to each other, consistent with the in vitro studies. In the early genital ridge, Sf1 expression precedes a low level of Sox9 expression in both sexes. The upregulation of Sox9 follows immediately the onset of Sry expression, whereas in the XX gonad, the extinction of Sox9 expression is remarkably consistent with the onset of Dax1 expression Fig.
However, XX mice deleted for Dax1 have normal ovaries and female reproductive tract, suggesting that it cannot be the only repressor of testis-specific genes in the early ovary Yu et al. In the male, the role of SRY would be to prevent this repression and perhaps to contribute directly to Sox9 activation. Once SOX9 levels reach a critical threshold, it could help maintain its own expression through an autoregulatory loop.
It is clearly important to characterize the regulatory regions of Sox9 in detail to see if any of this speculation is based in reality. Other candidate genes involved in sex determination are less characterized. Eicher and colleagues have identified three loci in mice that seem to modulate Sry action Eicher et al.
These studies employed the Sry gene from the Mus domesticus poschiavinus Y chromosome, which acts as a weak allele Sry pos. This works well enough on most genetic backgrounds, although testis differentiation can be delayed. The autosomal loci involved in this effect have been mapped to chromosome 4 tda-1 , 2 tda-2 , and 5 tda-3 Eicher et al. However, recent experiments suggest that the defect in Sry pos is at the transcriptional level as the amount of transcript present in the genital ridge is lower than that found with other Sry alleles C.
Nagamine, pers. Swain and R. Lovell-Badge, unpubl. It is clearly necessary to characterize the autosomal loci to really understand how they fit into the pathway. Once Sertoli cell fate is triggered by SRY, genes involved in Sertoli cell function become activated. One of these genes is Amh. The Amh gene is first expressed at 12 dpc in the developing Sertoli cells of the mouse testis in a pattern that closely follows the upregulation of Sox9 see Fig.
Munsterberg and Lovell-Badge ; Morais de Silva et al. A number of studies have focused on Amh gene regulation, however, most have relied on in vitro experiments and their conclusions await true in vivo validation. SAP62 is ubiquitously expressed, whereas Amh expression is tightly regulated. One in vivo study used base pairs upstream of the transcriptional start site of Amh linked to a heterologous marker, which was analysed in transgenic mice Giuili et al.
One out of the three transgenic lines that were analysed in this study was found to have marker expression restricted to the developing Sertoli cells. Within this Amh promoter region is a consensus binding site for SF1 Shen et al. When this binding site was mutated so that SF1 binding was abolished, and introduced into transgenic mice, no marker expression was observed in the embryonic testis three transgenic lines were analysed.
The numbers are low, but these results are consistent with the in vitro data, which shows that SF1 can bind and activate the Amh promoter. Although SF1 is a good candidate for an activator of Amh gene expression, it cannot account for its tissue specificity. SF1 is expressed in other cells where Amh is not, such as the embryonic Leydig and adrenal cells and in the developing ovary, although in this last case at lower levels.
The Amh promoter region also contains a consensus binding site for proteins containing an HMG box domain. In vitro studies have shown that SRY can bind to this sequence but only very weakly Haqq et al. Evidence from the developmental expression studies suggest that Amh is not a direct downstream target of SRY as the advent of Amh expression occurs at least 24 hr later than Sry and continues to be expressed throughout Sertoli cell differentiation when Sry transcripts are not present.
This is present in the male genital ridge at the time that Amh is activated and continues to be expressed in Sertoli cells throughout development and adulthood. Contrary to SF1, Sox9 is not expressed in the adrenal or Leydig cells and it is turned off in the female genital ridge at Consistent with this, recent in vitro evidence by de Santa Barbara et al.
Also, SOX9 can synergize SF1 activation of the Amh promoter suggesting that both factors act in concert to bring about tissue specific expression of Amh. WT1 has also been implicated in the regulation of Amh expression.
In this context, WT1 seems to be acting as a coactivator, as it is unable to activate or bind to Amh reporter constructs on its own.
Consistent with this, SF1 and WT1 proteins were found to interact directly, although this complex was not observed on the DNA in a gel shift assay. There is in vivo precedence for the involvement of WT1 in testis development: It is expressed in Sertoli cells of the developing testis and heterozygous Denys—Drash type mutations in humans will give rise to genital abnormalities with a higher frequency in males than in females. Also, these WT1 mutations are often associated with perstistent Mullerian duct structures in humans.
This suggests that the DNA-binding domain of WT1 is involved in the function of the protein as a coactivator. However, the domain that interacts with SF1 was mapped to the amino terminus. Contrary to what was expected from the dominant phenotype seen in Denys—Drash patients, the coactivating properties of wild-type WT1 were not affected by the presence of the mutant forms of WT1.
This suggests that the situation in these patients involves more that one mechanism of action by WT1. Further in vivo studies are needed to dissect the role of WT1 in Amh regulation and testis development and give insight into the cause of the diseases where this gene is involved. The role of DAX1 in early testis development and Amh regulation is unclear.
The transgenic experiments showed that DAX1 can be antagonistic to SRY action when expressed at high levels, but what is its normal role in testis development? DAX1 has been shown in vitro to function as a repressor in the context of SF1 mediated activation, with several studies suggesting that this occurs via protein-protein interaction Ito et al.
This suggests that it plays an inhibitory role in testis development and that significant levels of DAX1 should not be present in Sertoli cells if they are to produce AMH.
However, the results on this are inconsistent. Whole mount in situ hybridization showed that Dax1 expression is down-regulated in the developing testis at In agreement with this, porcine Dax1 is associated predominantly with the developing ovary, not the testis Pilon et al. Also, in a different set of experiments, when a region of the Dax1 gene was used to drive lacZ expression in mice, the gonadal expression was found to be consistent with that of the whole mount studies.
LacZ activity was highest at However, when radioactive in situ hybridization was used on sections of mouse gonads, which is probably a more sensitive technique, Dax1 transcripts were detected in the developing testis in a manner similar to that of SF1 Ikeda et al. Further studies using other techniques, such as immunocytochemistry with a DAX1 antibody, are necessary to resolve this inconsistency. The normal role for DAX1 in the ovary may be to prevent expression of genes such as Amh.
This would make sense, in that Dax1 expression is clearly maintained in the ovary at a time when Amh is expressed in the testis. However, recent results from gene targeting of Dax1 in mice suggest that DAX1 is not critical to repress Amh expression, as homozygous mutant females had normal Mullerian duct derivatives and were fertile Yu et al.
Therefore, even if DAX1 is involved, it can not be the only repressor. GATA4 protein binds to the consensus site in the Amh promoter and activates expression of a reporter construct in vitro.
The GATA4 expression pattern in the gonad, however, suggests that it might act at several levels in gonad development, furthermore, it alone can not be responsible for Amh regulation. High levels of GATA4 are present in the ovary up until 16 dpc. Mice deficient for GATA4 die in utero between 8.
Conditional mutations in GATA4 will be necessary to determine the role for this factor in gonad development in vivo. The interpretations of the data from the in vitro studies described above on WT1, GATA4, and SOX9 are tantalizing but carry the obvious caveats of these types of studies.
For example, the cell types used were not derived from embryonic gonads, the factors analysed were tested in isolation or together with SF1 only, and the role of a putative ligand for SF1 could not be assessed. Therefore it is dangerous to make hard conclusions based on these studies, but they do indicate directions that the in vivo studies should take to further our understanding.
After colonizing the genital ridge, the germ cells follow two different developmental pathways depending on the sex of the gonad they are in. In the early differentiating testis they go into mitotic arrest whereas in the early ovary they go into meiotic arrest.
When germ cells differentiate in ectopic tissues, such as the adrenal, where they sometimes migrate by mistake, they will go into meiotic arrest McLaren This suggests that these cells are programmed to arrest in meiosis and that the role of the embryonic testis is to produce a factor that will make them go into mitotic arrest and therefore trigger a spermatogenic fate.
The molecular nature of this factor is not known, but it is probably produced by the Sertoli cells. A central role of Sertoli cells is to sustain germ cells during development and later during spermatogenesis.
They do so by forming close cell—cell contacts and providing factors involved in growth and differentiation. A candidate factor involved in cell—cell interactions between Sertoli and germ cells is Desert hedgehog Dhh , a member of the hedgehog family of molecules that signal at close range. Expression studies have shown that it is present in male, but not female, gonads at Male mice deficient for Dhh are infertile owing to absence of sperm.
Analysis of the mutant mice showed that testis weights were reduced compared to wild-type mice from early embryonic stages. In later stages, histological analysis showed a germ cell deficiency and block in spermatogenesis that varied with the genetic background. However, the role of Dhh in the early testis has not been fully investigated.
It is unclear as to whether the reduction in size is due to a block in proliferation of germ cells or Sertoli cells or both. It is also possible that, in the testis, DHH could contribute to the signal that makes germ cells enter into mitotic arrest, whereas in its absence, cells go into meiotic arrest.
Meiotic germ cells are known to degenerate when in a testis, which is due at least in part to the action of AMH. If this is the case, the number of germ cells present in the Dhh -mutant testes would be reduced and this effect would account for some of the reduction of size in the embryological testis. This could be tested by looking for germ cells in meiotic arrest in the testis of mice that are deficient for both Dhh and Amh. Curiously, the putative receptor for the hedgehog family of proteins, patched, is expressed in interstitial cells of the developing testis and not germ cells, which implies that DHH acts indirectly on germ cells.
Once the Sertoli cells become determined they are thought to direct the differentiation of the rest of the testis. Very little is known about molecular candidates involved in this process. The Sertoli cells in the chimeric testis are mostly derived from the XY cells but a few XX Sertoli cells are also found. Sry is thought to determine Sertoli cells in a cell-autonomous manner, therefore Sertoli cells must then recruit XX cells to their fate through non-cell-autonomous products.
Candidates for these interaction factors are members of the wnt family of cell signaling molecules. A recent report by Vainio et al. In the ovary, the theca cells are not active until birth. XX mice that lack Wnt4 show activation of genes that code for enzymes involved in testosterone biosynthesis in the early ovary and masculinization of the Wolffian duct.
Wnt4 is expressed initially in the genital ridge and mesonephros but as gonad development proceeds it is downregulated in the testis but remains in the ovary. This suggests that Leydig cell precursors are present in the early genital ridge and that testosterone production in these cells is repressed by the presence of Wnt4. Sry then acts in the male, presumably through the determination of Sertoli cell fate, to downregulate Wnt4 expression and steroidogenesis is allowed to proceed.
A process known as Amniocentesis is done that examines the amniotic fluid which determines an abnormality in the fetus. This process also reveals the sex of the unborn child. Due to abortions of the female fetus in countries like India, the government has imposed a strict ban on this process of sex determination. In many western countries, sex determination is legal.
In humans and few insects like Drosophila, the females are denoted as XX. We can say that the females are homomorphic. In birds, the females are denoted as ZW and males as ZZ. So, in birds, the females are heteromorphic and the males are homomorphic. In humans, the mere absence of the Y chromosome makes the individual a female. Suggested Videos. Branches of Genetics. Evolution by Stages. Origin of Life and its Related Experiments H. Share with friends. Customize your course in 30 seconds Which class are you in?
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Sex determinationin biologyis a system which decides the sexual characteristics of an organism or offspring. It helps to determine whether the organism will be male or a female, which are the two most common sexes. The widely used technique is chromosomal sex determination, in determination sex chromosome of male i. X or Y chromosomedecides the sex or humans of the offspring.
Female carries XX chromosome and male carries Humans chromosome, in most cases. It is also determination to perform genetic tests to eliminate any chromosomal or genetic disorders. Sex determination determination the genetic process ppt determining the sex of the organism.
Let us study in more detail about this. Image source: study. Before we understand how sex determination is done, we need to understand the genetic makeup of determination human being. As we all know, humans have 23 pairs or 46 chromosomes. Humanz these 23 pairs, 22 pairs are known as autosomes whereas 1 pair is known as the sex chromosome.
It is this one pair that helps in determining the sex of an determination. This was first studied by the German scientist Hermann Henkingin It was named the X chromosome. He also noticed that a large number of determlnation had only one chromosome humans were sex as XO. Humans here began the studies on sex determination of ppt sexes in all determijation. Image humans deteemination. Females in humans have 2X ppt 1 each is inherited from either parent and denoted as XX. Males in humans have 1X and 1 Y chromosome, where the X is inherited from the mother and the Y from the father.
In a way, we can say that it is the father who determines the sex of the unborn child. This determination put to shame a lot of history in which people believed dex is the woman who was sex for not giving birth to a male heir.
We can also say that the absence of the Y chromosome ppt the individual a female. At the time of sex in malesboth types of gametes are produced- one carrying the X chromosome and one carrying the Y. At the time of fertilizationthe sex of the resulting zygote will depend on which humans of the father will fuse with the X of the mother.
It is important to note that pre-natal sex determination is an offense in many countries in the world, including India. A process determination as Amniocentesis is done that examines the amniotic fluid sex determines an abnormality in the fetus.
This process also reveals the sex of the unborn child. Due to abortions of the female fetus in countries like India, the government has imposed hu,ans strict ban on this process humans sex determination. Determniation many western countries, sex determination is legal. In humans and few insects like Ppt, the sex are denoted as XX.
We can say that the females are homomorphic. In determinatlon, the females are himans as ZW and males humxns ZZ. So, in birds, the females are ppt and the males are homomorphic. In humans, the mere absence of the Y chromosome makes the individual a female. Suggested Videos. Branches of Sez. Evolution by Stages. Origin sex Life and ppt Related Experiments H. Share with friends. Customize your course in sex seconds Which class are you in? This comment form is under antispam protection.
Notify of. Stuck with a Question Mark? Have a doubt at 3 am? Our experts are available humans. Connect with a tutor instantly and get determination concepts cleared ppt less than 3 steps. Download the App Watch lectures, practise questions and take tests on the pt.
Download Previous Years Question Papers. Do you want Question Papers of last swx years for free? Enter your phone number to get it.
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Sex Determination in Humans. • Chromosomal sex is determined at fertilization. • Sexual differences begin in the 7th week. • Sex is influenced by genetic and. 4 | Sex Determination and Sex-Linked Sex chromosomes and non-sex chromosomes (autosomes). XX-XO system: The male-determining gene in humans.
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