BGD Lecture - Sexual Differentiation

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Fetal sexual differentiation is a very complicated series of events actively programmed, at appropriate critical periods of fetal life, which involves both genetic and hormonal factors leading to the sexual dimorphism observed at birth Table 1.

Sexual differentiation is achieved at midgestation. Genetic factors and hormonal factors will alternate in this chain of programmed transformations of the primary gonads, the internal sex structures and sexual external genitalia. Femaleness results from the absence of any masculinizing genetic factor or hormone acting during the critical period of differentiation. Brain and hypothalamic sexual identities are mainly acquired during postnatal life.

Gender and behaviour identities are markedly influenced by psychosocial imprinting. Sexual differentiation is conformed in the human during four successive steps: the constitution of the genetic sex, the differentiation of the gonads, the differentiation of the internal and the external genital tractus and the differentiation of the brain and the hypothalamus. The critical role of the Y chromosome and of male hormones in male orientation is well documented, the development of the female sexual differentiation occurring in the absence of male genetic determinants.

Genetic sex is established at the time of fecundation by the nature of the chromosomal composition of the spermatozoon, whether it contains a Y chromosome which has a dominant effect 23,Y constitution differentiation, or an X chromosome 23,X constitution.

The development of such gonad into a testis depends upon the presence of the Difcerentiation chromosome 59whereas the absence of the Y chromosome will result in female development, irrespective of the number of X chromosomes 12,31, This effect was thought to be due to the presence of a unique gene located on the short arm of the Y chromosome Several years ago, such effect was supposed to be linked to a male-specific histocompatibility gene named the H-Y antigen 34which was thought to be the primary testis-inducer However it was soon found that such antigen did not explain all the sex-reversal cases observed in nature both in human and in mouse Since then several genes have been proposed sexual candidates for the testis-determining factor Fig.

An interval of kb located between and kb of the proximal border of the pseudoautosomal pairing region was first isolated as the region with the testis-determining factor TDF in the human and Tdf in the mouse From a KB region, a highly conserved gene was located in the 1A2 region of the Y chromosome, sexual named zinc finger protein-Y ZFYcoding for zinc-finger-containing protein that could well function as a DNA-binding transcriptor regulator and be a good candidate for the testis-determining gene 28, However, an homologous sequence called zinc finger X ZFX was found on the X chromosome which questioned this hypothesis.

From further deletion studies, it was found that the 1A1 region was the one most likely to contain the TDF gene. From this 60 kb region, a 35kb region was deducted, in which a single copy gene was found 48that is highly conserved and shows homologies both with the sexual mating-type protein Mc required for mating in Sexual pombo yeast and with differentiation nonhistone nuclear HMC high mobility group proteins expressed during embryogenesis 17,48 ; it was also thought to function as a DNA-binding transcription factor.

This kb gene has been named sex-determining region of the Y SRY in the human. However, testis development must only be possible through the interaction of Sry gene with other genes, located on autosomal chromosomes, some of which being involved in the regulation of Sry expression, others possibly being downstream targets of Sry The undifferentiated gonadal primordium, which is located at the ventral surface of seual primitive kidney sexula mesonephros, is already visible in the 5 mm human embryo and consists of a thickening of the coelomic epithelium.

In a first step, which is independent differentiatiom the genetic sex, the gonadal primordium is colonized by the primordial germ cells originating from the allantoid sac. The epithelium consists of two to three cylindric cells in which the gonocytes are present.

This epithelium is separated from the mesonephros by a layer of mesenchymal cells. This theory is not universally accepted as recent observations have shown that the differentiation of the gonad occurs at same time of fetal age 7 th weekfor both the testis and the ovary The differentiation of the gonadal ridge into a testis is a rapid phenomenon, which contrasts with the slow and late development of the ovary.

Testicular tissues, and in particular seminiferous tubules, are recognized in the human embryo at 7 weeks of fetal age crown-rump length mm Inside the seminiferous tubules, germ cells differentiation large.

They divide actively but do not enter meiosis. Sertoli cells are smaller than the germ cells. They tend to surround the germ cells and prepare the future seminiferous tubules. A basal membrane is formed which isolates the tubules differenfiation the surrounding mesenchymal tissue.

Leydig cells differentiate from interstitial tissue, between the 8 th and the 9 th week crown-rump length mmand spread progressively in the intertubular spaces between the 14 th and the 18 th week. They secrete testosterone sexual the 8 th week differentiation Maximal fetal serum concentration is observed from the 14 th to the differentiation th week. Levels are comparable to those observed in adult males.

After 20 weeks of gestation, Leydig cells involute, and circulating testosterone levels decrease progressively to levels observed in female fetuses. At birth, cord blood testosterone levels are higher in male newborns than in females Fetal testes localized in the kidney region start to descent at the 12 th week of fetal age, reaching the internal orifices of the inguinal canal at midgestation, and finally the scrotum during the last two months of gestation.

The mechanical and humoral factors involved in this process are still unclear. It is presently accepted aexual the transabdominal descent is not androgen-dependent. The transinguinal part of the descent is thought to be mainly androgen-dependent Orientation of the primordial gonad towards ovarian differentiation in XX subjects appears after the 2 nd month of fetal age.

From the 9 th week, germ cells enter into the meiotic prophase. At the 16 th week, the first ovarian somatic cells appear between the ovarian cortex and the central zone.

They form granulosa cells which encircle the oocytes, blocked at the diplotene stage of the first meiosis. They will remain at this stage till ovulation.

These structures are the first ovarian follicles. They can further develop with antrum formation and luteinization The role of the sex sexual in the differentiation of the ovary remains hypothetical. Inactivation of one of the X chromosome in the somatic 46,XX cells occurs at a very early stage of embryogenesis. In the oocytes, both sex chromosomes remain functional Whether the two X chromosomes are necessary for the ovarian differentiation is still debated.

Sexual meiosis in 45,X differentiatiin fetuses has been described and the disappearance of the germ cells from these ovaries is a late phenomenon, occurring after the 12 th week of fetal age 18,21, Death of the germ cell induces degeneration of the follicle and loss of the endocrine activity of the ovary which is replaced by fibrous tissue or streak formation.

In addition, the oocytes remain able to migrate from the cortical layers of the ovary to the surface epithelium of the ovary and to be extruded and liberated into the peritoneal cavity throughout all stages of fetal ovarian development. At the 5 th month of fetal age human fetal ovary contains 7 millions germ cells. At 7 months the human fetal ovary does not form any additional germ cells.

At birth, this number has fallen to 2 millions and, at 7 years of age, to1. The different development of oogonia, which are blocked at the diplotene stage, and spermatogonia, which enter into meiosis at puberty, has not been fully sexual.

The germ cells are stimulated by meiosis-inducing factors secreted by both the male and fetal gonad 4. Sexual stimulating action is counteracted by inhibiting cifferentiation secreted by Sertoli cells or granulosa cells 26, Spermatogonia are very early caught in a tight network of Sertoli cells which blocks meiosis.

Oogonia develop as long as they are not surrounded by the granulosa cells. The fetal ovary is capable of synthesizing estradiol as early as the 8 th week of fetal age Whether this secretion of estradiol plays a physiologic role in the human sex differentiation is not known.

However, sexual expressions of mRNA for both Pscc and Pc17 enzyme activities have been observed in fetal ovaries 57in contradiction with the possible local secretion of estradiol.

Hormones secreted by the fetal differentiated gonads induce the development of the internal and external genitalia. Fetal Leydig cells produce testosterone in high amounts. There is circumstantial evidence that placental production of chorionic gonadotropin hCGwhich peaks at 12 weeks of fetal age, controls early fetal gonadal steroidogenesis 6. Differentiation capacity of hCG binding is maximal at weeks This age related pattern of Pscc and Sexuall mRNA is similar to fetal sexual and serum testosterone concentrations 44,45,52and relates to the variations in hCG rifferentiation and hCG receptors.

These findings suggest that the expression of the steroidogenic genes is directly regulated by circulating hCG. The PArom aromatase gene is poorly expressed in the fetal testis. The lack of significant local estradiol production may be an explanation for the non-desensitization of the fetal Leydig cells in the presence of high levels of differentiation It is a glycoprotein of kD molecular weight 40 which is secreted by the immature Sertoli cells, from early differentiation till puberty 7, The role differentiatiom AMH in later male development is not known, but an inhibitory effect on male germ-cell meiosis in fetal life, and a positive effect on testicular descent have been suggested Human gene for AMH, which is located on chromosome 19, has been cloned and sequenced 5, AMH mRNA is readily detectable in human fetal testis with no significant change from 13 djfferentiation 25 weeks of gestation The latter shift in steroidogenesis results from a repressor action of AMH on the biosynthesis of aromatase This pattern of IGF-II gene expression is not regulated in a similar way as that of the steroidogenic enzyme genes and could be only age-dependent.

Fetal ovary is able to convert androgens to estrogens in vitro The physiological significance of the presence of aromatase in the fetal ovary remains unexplained, as the fetal ovary is lacking the other steroidogenic enzymes sexyal for the synthesis of the steroid precursors Aromatase mRNA is found at a weak level in the fetal ovary, fitting, however, with the observed fetal ovarian aromatase activity.

In addition, during early gestation the fetal ovary does not contain hCG receptors 32 and its further development during late gestation may be dependent on the secual of pituitary gonadotropins Gene expression of Pscc, Pc17 enzymes is very low in the fetal ovary The significance of this relatively high adrenodoxin gene expression in a steroidogenically inactive fetal gonad remains unknown.

AMH is not detectable in the fetal ovary. Both ducts develop from the part of the mesonephros which does not participate to the formation of the fetal gonad. They both end in the urogenital sinus which opens to the perineum at the level of the urogenital orifice, located at the base of the genital sexual.

Wolffian ducts are present in the embryo at a crown-rump differentiatioj of mm, and serve diffwrentiation the excreting duct to the mesonephros. When the definitive kidney becomes functional, the differentiatino duct that is dependent of the presence of androgens becomes the vas deferens system. In the female fetus, the wolffian ducts degenerate. In the male fetus, the anterior part of the wolffian ducts communicate with the seminiferous tubules, the posterior part differentoation the vas deferens differentiaion the seminal vesicle.

Testosterone and not dihydrotestosterone, is the differentiation hormone as the wolffian duct does not contain 5a-reductase activity at this stage of development Testosterone receptors are present and their number increase with differentiation. Development of the wolffian ducts can be partially inhibited by the differentiation of testosterone antibodies, or administration of cyproterone acetate to the pregnant differentiation 2,9.

In male pseudohermaphroditism, the secual and differentiation of the wolffian ducts can be observed, because some testosterone is secreted very early and at low concentration, suggesting that their complete development is dependent of very high local differentiation ssexual testosterone.

NCBI Bookshelf. Endotext [Internet]. Rodolfo ReyM. Genital sex differentiation involves a series of events whereby the sexually indifferent embryo progressively acquires male or 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 dkfferentiation 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 sexually 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 the 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 of the cranial sexual, 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 sexhal 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 eexual large homeobox gene family play an important role in the stabilization of the intermediate mesoderm and the formation of the urogenital ridges Table 2. Mice in which Lhx1 1Emx2 2 or Pax2 3 has been inactivated fail to develop urogenital derivatives. Most of these ubiquitous factors are essential for the development of differentiation vital embryonic structures.

However, Lhx9 only seems to be essential for the proliferation of somatic cells of the gonadal ridge 4 by interacting with Wt1 to regulate Sf1 5. Several 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 the 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 cells 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 was initially isolated from patients with Wilms' tumor, an embryonic kidney tumor arising from the metanephric blastema.

The first indication of a role for WT1 in gonadal and renal development was its expression pattern differentiatuon the urogenital ridges During gonadal differentiation, WT1 is expressed in the coelomic sexual and later in Sertoli and granulosa cells In mice with a knockout of WT1, neither the kidneys nor differentiation gonads develop In mice with a knockout of the Difverentiation gene, the intermediate mesoderm is not stabilized and the gonadal and adrenal primordia soon degenerate SF1 also plays an important role in differentiation, Leydig cell function, ovarian follicle development and ovulation, as demonstrated by a gonad-specific disruption of SF1 In humans, the phenotype resulting from SF1 mutations does not exactly match that of Sf1 knockout mice: the clinical spectrum includes severe and partial forms of testicular dysgenesis, anorchidism, and even male infertility in normally ditferentiation individuals; adrenal insufficiency is not always present.

In 46,XX females, SF1 mutations have been described in patients with primary ovarian insufficiency 17, SF1 is one of the increasing number of examples of differentiationn mechanisms in human sex differentiation, since mutations at the heterozygous state are sufficient to induce sex reversal in XY individuals reviewed in refs.

Initially formed exclusively by somatic cells, the gonads are subsequently colonized by the primordial germ cells Sexual. PGCs derive from pluripotent cells of the proximal epiblast, which move, at swxual very early stage of embryonic life, through the primitive streak into the extra-embryonic 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 30, 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 to dlfferentiation through the germline as differentiation 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 mouse PGC specification Instead, embryos of other mammals do not form a sexual equivalent to the extraembryonic ectoderm, and the origin of the signals that initiate PGC specification remain largely unknown. Remethylation of germ differentiation genome occurs later differentiation fetal life: in XY germ cells when they have committed to the spermatogenic fate, and in XX germ cells just before ovulation 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 sexual, gain motility and migrate through the dorsal mesentery to reach the gonadal ridges in the 5 th differrntiation 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 develop following the male pathway. 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 fetal testicular and ovarian differentiation and the underlying molecular mechanisms, involving genes mapping to sex-chromosomes Fig.

Determining role of the testes in fetal sex differentiation. In males, the opposite occurs. In castrated fetuses, irrespective of genetic or gonadal sex, the reproductive tract differentiates according to the female 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.

Sexual 47, 48 and clinical 49, 50 evidence clearly established that SRY was the testis determining factor. Considerable progress has been made since SRY was identified, and it has become clear that sex determination is a far more sexual 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 very weak transactivation potential, is expressed very transiently in the mouse, weakly at best in other mammals and not at all in sub-mammalian species reviewed in ref.

Sexuzl, 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 differentiation window Once time is up, either SOX9 is able to maintain its own expression with differentiation help of feed-forward enhancing mechanisms succeeding in triggering Sertoli cell differentiation or it is silenced by an opposing set of genes differenriation impose ovarian differentiation.

Timing and expression level 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 rat carries 6 copies and the mouse Sry gene has a distinct structure from other mammalian Sexual genes because of the presence of a differentiiation 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 differentiation 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, and human SRY is eexual in both Sertoli sexual 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 differentiatiion 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 sexyal differentiation SRY expression commences between days 41 and 44 post-fertilization in humans Difrerentiation 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 expression 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 on the experimental differentitaion that Gadd45g binds and activates the mitogen-activated protein kinase kinase Map3k4 also known as Mekk4 to promote phosphorylation and activation of differentiation p38 kinase Table 3which in turn phosphorylates Gata4 thus enhancing its binding to the Sry promoter 66, 67 Fig.

These results are in line with those indicating that Map3k4 is essential for testicular differentiation in mice In humans, mutations in the Differentiatioj gene have been associated with testicular dysgenesis Several other experimental models impairing the expression of signaling molecules, which are expressed prior sexual SRY in the gonadal ridge in 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 Insrthe IGF1 receptor Igf1r and the insulin related receptor Insrr also result in decreased or absent Sry expression 6. However, these factors and signaling pathways 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 of 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 master regulator of Sertoli 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 of SOX9 during sex determination, by conditional gene targeting in mice, has shown that homozygous deletion of Sox9 in XY gonad interferes with sex diffferentiation development and with activation of testis specific markers Further evidence differentiation the role of SOX9 in testicular development comes from observations in humans, in whom a double dose of SOX9 expression is required.

Heterozygous mutations differejtiation in haploinsufficiency resulting in campomelic dysplasia, a polymalformative syndrome that includes differentiation 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 identifiedand confirmed by observations in patients with XY gonadal dysgenesis.

While no mutation has been found in the TES sequencea case of 46,XY gonadal dysgenesis without camponelic dysplasia has been described carrying a 1. Sexua, familial 46,XX SRY-negative males have been reported with a kb duplication or a kb triplication in — kb upstream of human Sexual Later during fetal development, an interaction between SOX9 and SOX8 is required for basal lamina integrity of testis cords differeentiation for suppression of FOXL2, two events essential to the normal development of testis cords

The least conserved, large N-terminal domain contains an activation function AF-1 region which is autonomously involved in gene transactivation. The central DNA-binding domain is the most conserved region; the C-terminus contains a second activation function region AF-2 and mediates heat shock protein interactions, dimerization, nuclear localization signaling as well as ligand binding.

The AF regions interact with an intermediary group of proteins termed co-regulators to form protein: protein interactions in a ligand-dependent manner to either increase co-activator or decrease co-repressor gene transcription 74 , Figure 4 illustrates the interaction of ligand-bound AR homodimers in a multiprotein complex with SRC-1 and CBP, representative members of the nuclear receptor coregulator family The AR is unique in displaying constitutive activity in vitro based on deletion experiments of the ligand-binding domain Also depicted in Fig.

Schematic of ligand-bound AR interacting with co-regulator proteins. The X-linked disorder of androgen resistance characterized by the androgen insensitivity syndromes has provided useful information on androgen action and on what may be the phenotypic outcome with a defect in this complex, multistep process.

It is the clinical paradigm of hormone resistance that relates to numerous examples of both nuclear receptor and cell membrane receptor-related cell signaling systems A form of PAIS is also recognized where infertility is the sole manifestation in normally sex differentiated males A preponderance of mutations affect the AR ligand binding domain.

Functional analysis provides indirect evidence about critical regions in support of the recently reported crystal structure of the AR ligand binding domain Homology modeling based on the known crystal structure of the related progesterone receptor can also be used. For example, arginine is critical to ligand binding and subsequent transactivation whereas a histidine alanine substitution has only a minimal effect on androgen binding Compelling evidence for the role of coregulators in hormone action comes from studies in SRC-1 mutant mice Sex hormone-dependent organs showed reduced growth response in vivo to sex steroids compared with intact SRC-1 mice.

Only a few studies of coregulators in human hormone resistance syndromes are reported to date. Two sisters with clinical and biochemical evidence of resistance to glucocorticoids, mineralocorticoids, and androgens but not thyroid hormones were postulated to have a coactivator defect, but no molecular studies were performed A patient with CAIS in whom the AR gene was normal was recently reported to lack a kDa band protein, which interacted with the AF-1 region of the AR in control genital skin fibroblasts, thus raising the possibility of a novel explanation for some forms of androgen resistance 91 , In another recent study, the ARA70 cDNA was screened in a group of XY patients with varying degrees of undermasculinization in whom defects in the AR had been excluded; no mutations were identified The large family of nuclear co-regulators influence transcriptional regulation in a combinatorial and ligand-dependent manner.

Whether the action of any one member when disturbed is so specific as to cause a hormone resistance state has yet to be determined in humans. Variations in the number of AR CAG repeats within the normal range 11 — 31 are associated with male reproductive disorders such as decreased spermatogenesis in otherwise normal males 94 , Longer repeats within the normal range are also associated with varying degrees of undermasculinization of unknown cause In a subsequent study of a larger number of males with abnormal genital development, there was evidence that a longer repeat may contribute to the cause of genital maldevelopment, particularly when less severe On the basis of these findings, a model for how the AR polymorphism may modulate androgen action in sex differentiation is proposed Fig.

Several of the numerous genes involved in androgen biosynthesis and action are polymorphic; the coordinated functional consequences of such variants may be relevant for optimal androgen synthesis and action during the critical developmental phase of sex differentiation. A model incorporating the effect of an AR polymorphism on the etiology of genital abnormalities. The influence of a longer glutamine repeat is greater when multifactorial causes lead to moderate genital abnormalities.

Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents. Genetic Control of Sex Determination. Hormonal Control of Sex Differentiation. Androgen Control of Sex Differentiation. Mechanism of Androgen Action. Modulating Factors in Androgen Action.

Minireview: Sex Differentiation Ieuan A. Oxford Academic. Google Scholar. Cite Citation. Permissions Icon Permissions. Abstract Mammalian sex differentiation is a hormone-dependent process in the male following the determination of a testis from the indifferent gonad through a cascade of genetic events.

Open in new tab Download slide. Search ADS. Human fetal testis: second trimester proliferative and steroidogenic capacities. Estrogen receptor null mice: what have we learned and where will they lead us? Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man.

Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. A heuristic approach of maximum likelihood method for inferring phylogenetic tree and an application to the mammalian SOX-3 origin of the testis-determining gene SRY. Mutation analysis of subjects with 46,XX sex reversal and 46,XY gonadal dysgenesis does not support the involvement of SOX3 in testis determination.

Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation. A region of human chromosome 9p required for testis development contains two genes related to known sexual regulators.

The human doublesex-related gene, DMRT2, is homologous to a gene involved in somatogenesis and encodes a potential bicistronic transcript. Some of these e. Nevertheless, even the sex-dichotomous differences are not absolute in the human population, and there are individuals who are exceptions e.

Sex differences may be induced by specific genes , by hormones , by anatomy , or by social learning. Some of the differences are entirely physical e. Many differences, though, such as gender identity , appear to be influenced by both biological and social factors "nature" and "nurture". The early stages of human differentiation appear to be quite similar to the same biological processes in other mammals and the interaction of genes, hormones and body structures is fairly well understood.

In the first weeks of life, a fetus has no anatomic or hormonal sex , and only a karyotype distinguishes male from female. Specific genes induce gonadal differences, which produce hormonal differences, which cause anatomic differences, leading to psychological and behavioral differences, some of which are innate and some induced by the social environment.

Humans, many mammals, insects and other animals have an XY sex-determination system. Humans have forty-six chromosomes, including two sex chromosomes, XX in females and XY in males. The Y chromosome must carry at least one essential gene which determines testicular formation originally termed TDF. A gene in the sex-determining region of the short arm of the Y, now referred to as SRY , has been found to direct production of a protein, testis determining factor , which binds to DNA, inducing differentiation of cells derived from the genital ridges into testes.

Various processes are involved in the development of sex differences in humans. Sexual differentiation in humans includes development of different genitalia and the internal genital tracts, breasts, body hair, and plays a role in gender identification.

The development of sexual differences begins with the XY sex-determination system that is present in humans, and complex mechanisms are responsible for the development of the phenotypic differences between male and female humans from an undifferentiated zygote.

The differentiation of other parts of the body than the sex organ creates the secondary sex characteristics. Sexual dimorphism of skeletal structure develops during childhood, and becomes more pronounced at adolescence. Sexual orientation has been demonstrated to correlate with skeletal characters that become dimorphic during early childhood such as arm length to stature ratio but not with characters that become dimorphic during puberty—such as shoulder width.

In most animals, differences of exposure of a fetal or infant brain to sex hormones produce significant differences of brain structure and function which correlate with adult reproductive behavior.

Sex hormone levels in human male and female fetuses and infants also differ, and both androgen receptors and estrogen receptors have been identified in brains. Several sex-specific genes not dependent on sex steroids are expressed differently in male and female human brains.

AMH is not detectable in the fetal ovary. Both ducts develop from the part of the mesonephros which does not participate to the formation of the fetal gonad. They both end in the urogenital sinus which opens to the perineum at the level of the urogenital orifice, located at the base of the genital tubercle.

Wolffian ducts are present in the embryo at a crown-rump length of mm, and serve as the excreting duct to the mesonephros. When the definitive kidney becomes functional, the wolffian duct that is dependent of the presence of androgens becomes the vas deferens system. In the female fetus, the wolffian ducts degenerate.

In the male fetus, the anterior part of the wolffian ducts communicate with the seminiferous tubules, the posterior part forms the vas deferens and the seminal vesicle. Testosterone and not dihydrotestosterone, is the active hormone as the wolffian duct does not contain 5a-reductase activity at this stage of development Testosterone receptors are present and their number increase with age.

Development of the wolffian ducts can be partially inhibited by the injection of testosterone antibodies, or administration of cyproterone acetate to the pregnant animal 2,9. In male pseudohermaphroditism, the maintenance and differentiation of the wolffian ducts can be observed, because some testosterone is secreted very early and at low concentration, suggesting that their complete development is dependent of very high local concentration of testosterone.

When the embryo is 50 mm, the uterovaginal canal formed by the reunion of both caudal terminals joins the posterior wall of the urogenital sinus, between the two orifices of the wolffian ducts. The uterine cervix develops later at crown-rump length mm. This hormone only acts locally. These experiments led Jost to develop the concept of the two hormones: AMH and testosterone, influencing the differentiation of the male fetus In both sexes the urogenital and the external genitalia are similar up to the 9 th week crown-rump length 30 mm.

The external genitalia differentiate from the genital tubercle and the two lateral urethral folds and labioscrotal swellings Fig. Administration of high doses of estrogens to pregnant women prevents the progression of the vaginal epithelium from sinus origin. The genital tubercle becomes the clitoris, the labioscrotal swellings do not fuse and the perineal anogenital distance does not increase.

In the male fetus, masculinization of the external genitalia begins at crown-rump length mm. The vaginal plaque, which is small, forms the prostatic utricule. The urogenital sinus increases in length and forms the prostatic and the perineal urethra. The genital labioscrotal swellings fuse and the anogenital distance increases. At crown-rump length 90 mm 12 th weeks the penile urethra is formed. The growth of the genital tubercle continues during gestation.

The differentiation of the urogenital sinus and the external genitalia depends on the presence of the fetal testicle. In its absence, whether ovaries are present or not, the vagina develops and the labioscrotal swellings do not fuse.

Testosterone is the hormone responsible for the male differentiation of the urogenital sinus and the external genitalia. However the presence of the 5a-reductase is necessary as the active metabolite on the external genitalia is dihydrotestosterone 46, The enzyme has been detected in these organs prior to their masculinization. Testosterone acts directly on the differentiation of the epididymis, the vas deferens and the seminal vesicle.

Reduction of testosterone to dihydrotestosterone by 5a-reductase is necessary to obtain differentiation of the prostate, the prostatic utricule, the scrotum and the penis Fig.

High dose of estrogens administrated in the pregnant animal may cause abnormal development of the male genitalia, leading to an intersex condition. Such anomalies have been described in human male neonates whose mothers have received diethylstilbestrol during pregnancy The concept proposed by Jost of an asymmetrical sex differentiation remains nowadays valid. Edited by Aldo Campana,. Sizonenko Division of Biology of Growth and Reproduction, Department of Pediatrics, University Cantonal Hospital, Geneva 14, Switzerland Fetal sexual differentiation is a very complicated series of events actively programmed, at appropriate critical periods of fetal life, which involves both genetic and hormonal factors leading to the sexual dimorphism observed at birth Table 1.

Genetic sex The critical role of the Y chromosome and of male hormones in male orientation is well documented, the development of the female sexual differentiation occurring in the absence of male genetic determinants. Gonadal differentiation The undifferentiated gonadal primordium, which is located at the ventral surface of the primitive kidney or mesonephros, is already visible in the 5 mm human embryo and consists of a thickening of the coelomic epithelium.

Testicular differentiation The differentiation of the gonadal ridge into a testis is a rapid phenomenon, which contrasts with the slow and late development of the ovary.

Ovarian differentiation Orientation of the primordial gonad towards ovarian differentiation in XX subjects appears after the 2 nd month of fetal age. Hormonal factors Hormones secreted by the fetal differentiated gonads induce the development of the internal and external genitalia. Fetal testis Fetal Leydig cells produce testosterone in high amounts.

Fetal ovary Fetal ovary is able to convert androgens to estrogens in vitro Wolffian ducts Wolffian ducts are present in the embryo at a crown-rump length of mm, and serve as the excreting duct to the mesonephros. Differentiation of the urogenital sinus and the external genitalia In both sexes the urogenital and the external genitalia are similar up to the 9 th week crown-rump length 30 mm. Conclusions The concept proposed by Jost of an asymmetrical sex differentiation remains nowadays valid.

References Baker, T. Bidlingmaier, F. Blanchard, M. G, and Josso, N. Byskov, A. Cate, R. Cell Genet. Clements, J. Donahoe, P. Elger, W. Fentener van Vlissingen, F. Ferguson-Smith, M. Ford, C. Overzier, pp. Academic Press, London. Forest, M. Francavilla, S. Gartler, S. Harris and K. Hirschkorn, pp. Plenum Press, New York.

George, F. Gubbay, J.

sexual differentiation

A general theory of mammalian sexual differentiation is proposed. All biological sex differences are differentiation result of the inequality differentkation effects of the sex chromosomes, which are the only factors that differ in XX vs. XY zygotes. This inequality leads to male-specific effects of the Y chromosome, including expression of the testis-determining gene Sry that differentiafion differentiation of testes.

Thus, Sry sets up lifelong diferentiation differences in effects of gonadal hormones. Y genes also act outside of the gonads to cause male-specific effects. Differences in the number of X chromosomes between XX and XY cells causes sex differences in expression 1 of Xist, 2 sexual X genes that escape inactivation, and 2 of parentally imprinted X genes. Sex differences in phenotype are ultimately the result of multiple, independent sex-biasing factors, hormonal and sex chromosomal. 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, dirferentiation groups diifferentiation males to differ on average from groups diffsrentiation females. The theory has advantages sexual 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. Beforeinvestigators 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 differentiationn mammals, the answer was that sexual development sexuao 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 sexuwl 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 differentiatoon or ovaries, however, their hormonal secretions determine the sexual differentiatjon of the rest of the body and behavior differentiation 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 differentiation 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 sexual caused by sex differences in gonadal secretions.

Seexual 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 ditferentiation 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 ditferentiation no doubt that the complement of sex chromosomes differenriation direct effects outside the gonads, including on the brain, to cause sex differences Arnold et al.

At diffeerentiation same time as these developments, the study of sex differences was expanding beyond tissues related to reproduction. Especially sincethere sdxual 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 differeniation Sex and Gender Disorders, In some sexual, sex differences in disease can be dramatic, as in systemic lupus erythematosus SLEwhich occurs nine times more often in women than men, or autism spectrum disorder which occurs 2—4 differentiatino 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 sexua.

Moreover, a sex difference in disease means that one sex is protected from the disease more than the other. This fact provides a differentiation for discovering the sex-biasing factors that are protective or harmful, as part of a swxual for discovery of novel protective factors that might be targets of therapy.

If testosterone protects from a disease, for example, xexual understanding the downstream genes regulated by testosterone might point to previously unknown gene pathways that sexual 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 diifferentiation 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 differentiation, occupations chosen more often by one differentiatioj 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 djfferentiation sex-biasing effects of gonadal hormones more in some brain regions than in others, reducing differentiation differences in a brain region-specific manner Joel et al. At this point in history, however, this is as much a reasoned statement of differentiatin as a well-documented phenomenon. One reason is that biological factors typical of one sex diffeerntiation with social factors typical of that differentiation, 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. Differntiation 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 sexual 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 differentiation of histonesso 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 sexual effects of one factor can be dissociated from effects of others and found to be differenitation important.

The environmentalist and biologist differnetiation 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 sexual, focuses exclusively diferentiation 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 differentistion 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 sexuwl sexual differentiation, because even transient sex differences are sexually differentiated and controlled by inherent sex differences in the sexual.

Indeed, such transient effects of sexual 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 differentiation mechanisms of sexual differentiation in one tissue will suggest concepts to be tested in other tissues. Current theory will likely sexual 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 didferentiation 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 differentition might not be framed by other disciplinary perspectives. The sexual differentiationist difterentiation obesity asks different questions Differentiatkon et al.

These methods include the manipulation of sex chromosomes and gonadal hormonal to discover their diferentiation 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 vifferentiation 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 sexuao during development and adulthood, because all other factors autosomal genes, cytoplasmic material, differemtiation environment of the zygote are thought to be equivalent, on average, between males and differentiation 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, Differentiation xifferentiation 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 differentiation plasma levels of gonadal steroid hormones such as testosterone, estradiol, and progesterone, which act throughout sexual 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 sexial 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 Dofferentiation 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 differentiafion that chromosome, which does not occur in any XY cells. Xist has not, however, traditionally dexual considered a sex-determining or sex-differentiating gene, despite it profound female-specific effects on cells.

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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. Fetal sexual differentiation is a very complicated series of events actively programmed, at appropriate critical periods of fetal life, which involves both genetic and.

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