Disorders in human sex differentiation.
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Biological Phenomena↗
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Results for “Sex Determination Processes”
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Expression and subcellular localization of SF-1, SOX9, WT1, and AMH proteins during early human testicular development.
Many transcription factors have been identified and implicated in male sex determination pathway. Specifically involved in Sertoli cell differentiation and subsequent anti-Müllerian hormone (AMH) secretion in eutherian mammals, they include steroidogenic factor-1 (SF-1), SOX9 (SRY HMG box related gene 9), WT1 (Wilms' tumor 1), and GATA-4 (a zinc finger transcription factor). These factors have been described to execute their function in the male sex determination pathway by controlling AMH transcriptional expression. To understand the hierarchies of these factors and their involvement in the developing testis, for the first time we show the expression and subcellular localization of these factors by immunohistochemistry in the early human testis during embryogenesis compared with AMH expression. If these studies do not refute their possible synergistic interaction to control AMH expression in human embryo, they also reveal a new sexual dimorphism in SOX9 expression during the sex determination process. We show that SOX9 sex specifically shifts from the cytoplasmic to the nuclear compartment at the time of testis differentiation and AMH expression. Putative models for this subcellular distribution are discussed.
Anti-Mullerian Hormone↗
New insights into the regulation of mammalian sex determination and male sex differentiation.
In mammals, sex development is a genetically and hormonally controlled process that begins with the establishment of chromosomal or genetic sex (XY or XX) at conception. At approximately 6 to 7 weeks of human gestation or embryonic day e11.5 in the mouse, expression of the Y chromosome-linked sex determining gene called SRY (described in detail in this chapter) then initiates gonadal differentiation, which is the formation of either a testis (male) or an ovary (female). Male sex differentiation (development of internal and external reproductive organs and acquisition of male secondary sex characteristics) is then controlled by three principal hormones produced by the testis: Mullerian inhibiting substance (MIS) or anti-Mullerian hormone (AMH), testosterone, and insulin-like factor 3 (INSL3). In the absence of these critical testicular hormones, female sex differentiation ensues. This sequential, three-step process of mammalian sex development is also known as the Jost paradigm. With the advent of modern biotechnologies over the past decade, such as transgenics, array-based gene profiling, and proteomics, the field of mammalian sex determination has witnessed a remarkable boost in the understanding of the genetics and complex molecular mechanisms that regulate this fundamental biological event. Consequently, a number of excellent reviews have been devoted to this topic. The purpose of the present chapter is to provide an overview of selected aspects of mammalian sex determination and differentiation with an emphasis on studies that have marked this field of study.
Animals↗
46,XX sex reversal.
In humans, sexual differentiation is directed by SRY, a master regulatory gene located at the Y chromosome. This gene initiates the male pathway or represses the female pathway by regulating the transcription of downstream genes; however, the precise mechanisms by which SRY acts are largely unknown. Moreover, several genes have recently been implicated in the development of the bipotential gonad even before SRY is expressed. In some individuals, the normal process of sexual differentiation is altered and a sex reversal disorder is observed. These subjects present the chromosomes of one sex but the physical attributes of the other. Over the past years, considerable progress has been achieved in the molecular characterization of these disorders by using a combination of strategies including cell biology, animal models, and by studying patients with these pathologic entities.
Animal Diseases↗
Sexual development in marsupials: genetic characterization of bandicoot siblings with scrotal and testicular maldevelopment.
In marsupials testis determination requires the presence of a Y chromosome. The sex determining region on the Y gene (SRY) is necessary for testicular development in eutherians and it is assumed to play a similar role in marsupials. Relatively few studies have investigated the genetic basis of sexual development, and as yet there is no direct evidence that SRY is required for testis development in marsupials. Studies on intersexual marsupials have revealed a fundamental difference between marsupial and eutherian sex determination. The scrotum of marsupials is analogous, not homologous, to the eutherian scrotum and is under the control of X-linked genes not androgens. The current study describes two bandicoot (Isoodon macrourus) siblings. Both siblings had underdeveloped male reproductive tracts and testicular dysgenesis, one was ascrotal and the other had a diminutive scrotum. Their karyotypes were normal for this species which eliminates the Y chromosome from some somatic tissues. SRY was detected by Southern blotting. SRY, ubiquitin activating enzyme-1 on the Y (UBE1Y) and glucose 6-phosphate dehydrogenase (G6PD) gene expression were examined. UBE1Y was widely expressed in many tissues. SRY gene expression was much lower than normal in the abnormal siblings and may be responsible for their failure of testicular and epididymal development. The cause of their scrotal abnormalities is unknown. It is possible that the separate defects of scrotal and testis development in the two siblings, which had normal relatives, were due to a mutation in a gene common to both developmental pathways.
Animals↗
Regulation of male sexual development by Sry and Sox9.
Sry, a gene from the Y chromosome, is known to initiate testis formation and subsequent male differentiation in mammals. A related gene, Sox9, also plays a critical role in testis determination, possibly in all vertebrates. A number of models have been presented regarding the molecular modes of action of these two genes. However, details regarding their regulation, regulatory target genes, and interacting protein factors and co-factors have not been established with any certainty. In this review, we examine new evidence and re-examine existing evidence bearing on these issues, in an effort to build up an integrative model of the network of gene activity centred around Sry and Sox9. J. Exp. Zool. 290:463-474, 2001.
Animals↗
Expression of the human SRY protein during development in normal male gonadal and sex-reversed tissues.
Sex determination in mammals is controlled by the SRY gene located on the Y chromosome. It encodes a protein containing a DNA-binding and DNA-bending domain. In spite of recent advances in the identification of the mechanisms that regulate male sex determination in mammals, the expression profile of the SRY protein in normal and sex-reversed human tissues is not well established. In order to localize the SRY protein and determine its cellular distribution and expression at different stages of development, we prepared monoclonal antibodies (mAb) against the recombinant SRY protein. One of these antibodies, LSRY1.1, recognizes a protein of 27 kDa in total lysates of HeLa SRYB3, a human cell line transfected with the SRY gene under the control of the SV40 promoter. Immunocytochemical analysis in the cell lines shows nuclear localization of the SRY protein. We have studied SRY protein expression in human tissues at different stage of fetal development until adult life and have demonstrated that the SRY protein is located in the nuclei of somatic cells and germ cells in the genital ridge during testis development. After testis determination, it can be detected until the adult stage in both germ cells and Sertoli cells. The presence of the SRY protein was also analyzed in biopsies of gonadal tissues of sex-reversal patients such as SRY-positive 46,XX males or SRY-positive 46,XX true hermaphrodites. SRY protein is detected in the nuclei of Sertoli cells of the testis and in the nuclei of granulosa cells in the ovotestis in these patients and in the nuclei of germ cells of both tissue types. These results suggest a common cellular origin for both Sertoli cells and granulosa cells.
Adolescent↗
Sry and Sox9 expression during canine gonadal sex determination assayed by quantitative reverse transcription-polymerase chain reaction.
Testis induction is associated with gonadal Sry and Sox9 expression in mammals, and with Sox9 expression in vertebrates where Sry is absent. In mammals, Sry might initiate testis induction by upregulating Sox9 expression; however, direct evidence supporting this hypothesis is lacking. Models of Sry-negative XX sex reversal (XXSR), in which testes develop in the absence of Sry, could provide the link between Sry and Sox9 in testis induction. To define the stages at which testis determination occurs in the canine model, Sry and Sox9 expression were measured in normal urogenital ridges (UGR) and gonads by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Testicular Sry expression rose continuously during canine developmental ages comparable to human carnegie stages (CS) 16-18, with maximal expression at CS 18. Sox9 was expressed in both male and female canine UGR up to CS 17, at which time testis expression became tenfold greater than in the ovary. Although Sox9 was detected by qRT-PCR in ovaries and mesonephroi of both sexes, expression was detected only in canine testes by whole mount in situ hybridization (WMISH). The timing of Sry and Sox9 expression is consistent with a role in testis determination: Sry expression begins at CS 16 in testes, followed by upregulation of Sox9 expression at CS 17. The quantity and temporal and spatial patterns of Sry and Sox9 expression in normal canine gonads are similar to those in humans, sheep, and pigs. These studies should provide the basis for understanding the mechanism of testis induction in the canine model of Sry-negative XXSR.
Amino Acid Sequence↗
Mammalian sex determination: from gonads to brain.
In mammals, sex is determined by the Y chromosome, which encodes a testis-determining factor (TDF). This factor causes the undifferentiated embryonic gonads to develop as testes rather than ovaries. The testes subsequently produce the male sex hormones that are responsible for all male sexual characteristics. In 1990, the sex-determining gene, TDF, was identified and termed SRY in humans (Sry in mice). It encodes a protein containing a high mobility group (HMG) motif, which confers the ability to bind and to bend DNA. Genetic evidence supporting SRY as TDF came from the observation of a male phenotype in XX mice transgenic for a small genomic fragment containing Sry, and from the study of XY sex-reversed individuals who harbor de novo mutations in the SRY coding sequence. Other non-Y-linked genes involved in sex determination were subsequently found by genetic analysis of XY sex-reversed patients not explained by mutations in SRY. These genes are WT1, SF1, DAX1, and SOX9. A regulatory cascade hypothesis for mammalian sex determination, proposing that SRY represses a negative regulator of male development, was recently supported by observation of mice that expressed a DAX1 transgene and developed as XY sex-reversed females. The role of some sex-determining genes, such as DAX1 and SF1, in the development of the entire reproductive axis, a functionally integrated endocrine axis, leads to a new concept. Normal sexual development may result from the functional and developmental integration of a number of different genes that play roles in sex determination, sexual differentiation, and sexual behavior.
Amino Acid Sequence↗
Genetics of sex determination: exceptions that prove the rule.
The dogma that male and female embryos develop in identical fashion until SRY initiates Sertoli cell differentiation in the hitherto bipotential gonad is in need of reevaluation in the light of data that do not fit into this scheme. One of the exceptions that proves the rule of sex determination is true hermaphroditism, the existence of individuals with both testicular and ovarian tissue. Furthermore, the two types of tissues are asymmetrically distributed, ovaries being more common on the left side and testes and ovotestes on the right. Hermaphrodite mice also exhibit bilateral asymmetry of gonad differentiation, but in the opposite direction: ovaries on the right, testes and ovotestes on the left. To explain these asymmetries, it is necessary to consider the relationship between growth and gonadal differentiation. The idea that accelerated growth precedes histological differentiation of the testis has recently been confirmed by the finding that Sry induces cell proliferation in fetal mouse gonads, suggesting that the differentiation of Sertoli cells may be dependent on a critical cell number. Recent evidence has also shown that XY embryos develop faster than their XX counterparts at very early stages of development, and it has been reported that SRY and ZFY are expressed in early human and murine embryos. The relationship between growth and sex differentiation links the mammalian system with those of nonmammalian vertebrates with temperature-dependent sex determination. Early growth differences between male and female human embryos question the belief that all sex differences in later life are due to gonadal hormones.
Animals↗
Sry, Sox9 and mammalian sex determination.
Sry is the Y-chromosomal gene that acts as a trigger for male development in mammalian embryos. This gene encodes a high mobility group (HMG) box transcription factor that is known to bind to specific target sequences in DNA and to cause a bend in the chromatin. DNA bending appears to be part of the mechanism by which Sry influences transcription of genes downstream in a cascade of gene regulation leading to maleness, but the factors that cooperate with, and the direct targets of, Sry remain to be identified. One gene known to be downstream from Sry in this cascade in Sox9, which encodes a transcription factor related to Sry by the HMG box. Like Sry, mutations in Sox9 disrupt male development, but unlike Sry, the role of Sox9 is not limited to mammals. This review focuses on what is known about the two genes and their likely modes of action, and draws together recent data relating to how they might interconnect with the network of gene activity implicated in testis determination in mammals.
Amino Acid Sequence↗
The cell biology and molecular genetics of testis determination.
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Animals↗
The one-to-four rule and paralogues of sex-determining genes.
Because of two successive rounds of tetraploidization at their inception, the vertebrates contain four times more protein-coding genes in their genome than the invertebrates: 60,000 versus 15,000. Consequently, each invertebrate gene has been amplified to the maximum of four paralogous genes in vertebrates: the one-to-four rule. When this rule is applied to genes pertinent to gonadal development and differentiation, the following emerged: (i) Two closely related zinc-finger transcription factor genes in invertebrates have been amplified to two paralogous groups in vertebrates. One consisted of EGR1, EGR2, EGR3 and EGR4, whereas the only known paralogue of the other is WT1, which controls the developmental fate of the entire nephric system, and therefore of gonads. Interestingly, EGR1 and WT1 act as antagonists of each other in nephroblastic cells. (ii) SF-1, which controls the fate of two steroid hormone-producing organs, adrenals and gonads, is descended from the invertebrate Ftz-F1 gene, and its only known paralogue is GCNF-1. (iii) The Y-linked SRY, the mammalian testis-determining gene, is a paralogue neither of SOX3 (SRX) nor of SOX9. Its ancient origin suggests that SRY once became extinct in earlier vertebrates, only to revive itself in the mammalian ancestor. (iv) Inasmuch as four paralogues of one invertebrate nuclear receptor gene have differentiated to receptors of androgen, mineralocoticoid, glucocorticoid and progesterone, there should at most be four paralogous estrogen-receptor genes in the vertebrate genome. It is likely that one of them plays a pivotal role in the estrogen-dependent sex-determining mechanism so commonly found among reptiles, amphibians and fish.
Adrenal Cortex↗
Genes essential for early events in gonadal development.
The acquisition of a sexually dimorphic phenotype is a critical event in mammalian development. The basic underlying principle of sexual development is that genetic sex-determined at fertilization by the presence or absence of the Y chromosome--directs the embryonic gonads to differentiate into either testes or ovaries. Thereafter, hormones produced by the testes direct the developmental program that leads to male sexual differentiation. In the absence of testicular hormones, the female pathway of sexual differentiation occurs. Recent studies have defined key roles in gonadal development for two transcription factors: Wilms' tumor suppressor 1 (WT1) and steroidogenic factor 1 (SF-1). After presenting a brief overview of gonadal development and sexual differentiation, this paper reviews the studies that led to the isolation and characterization of WT1 and SF-1, and then discusses how interactions between these two genes may mediate their key roles in a common developmental pathway.
Animals↗
Sex chromosomes and sex-determining genes: insights from marsupials and monotremes.
Comparative studies of the genes involved in sex determination in the three extant classes of mammals, and other vertebrates, has allowed us to identify genes that are highly conserved in vertebrate sex determination and those that have recently evolved roles in one lineage. Analysis of the conservation and function of candidate genes in different vertebrate groups has been crucial to our understanding of their function and positioning in a conserved vertebrate sex-determining pathway. Here we review comparisons between genes in the sex-determining pathway in different vertebrates, and ask how these comparisons affect our views on the role of each gene in vertebrate sex determination.
Animals↗
Male sex determination in the spiny rat Tokudaia osimensis (Rodentia: Muridae) is not Sry dependent.
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Animals↗
Sex is a threshold dichotomy mimicking a single gene effect.
The discovery of SRY ended the search for the male-determining gene, but the much sought after molecular pathway that connects the gene to its phenotype remains elusive. It is timely, therefore, to consider an alternative route of inheritance that can simulate mendelian segregation. The term "threshold dichotomy" is applied to contrasting phenotypes that have their origin in multiple genes with quantitative effects and are divided by a physiological threshold. I suggest that this mechanism provides a plausible basis for male development in mammals, which is known to depend on enhanced rates of cell proliferation in the developing embryo and can be expected to require increased levels of cellular energy. The system is affected by the genetic and environmental background. I also propose that the Y chromosome minimizes the effects of these variables on XY embryos so that, barring rare exceptions, the inheritance of sex resembles a single gene effect.
Chromosomes, Human, Y↗
SOX9 is up-regulated by the transient expression of SRY specifically in Sertoli cell precursors.
The Y chromosome gene Sry encodes a transcription factor required to initiate testis development. The related autosomal gene Sox9 is up-regulated shortly after the onset of Sry transcription and is thought essential for the differentiation of Sertoli cells. The lineage that gives rise to Sertoli cells has its origins within the coelomic epithelium (CE) of the genital ridge, but from cells also able to give rise to an interstitial cell type. It was not known at what point SRY acts in the derivation of this lineage or how the two genes interact. To investigate the identity of the cells expressing Sry, we designed two transgenes driven by the Sry promoter: one gives expression of a stable reporter, human placental alkaline phosphatase (hPLAP), while the second gives expression of a functional Myc-epitope tagged SRY protein (SRYMYC). Taking advantage of lasting hPLAP activity after transcription of the reporter gene has ceased, we could show that SryhPLAP was expressed exclusively in all cells fated to become Sertoli cells. SRYMYC-single-positive cells were first observed in the gonad and not in the CE. Subsequently, they became SRYMYC/SOX9-double-positive, but only for a few hours before turning into SOX9-single-positive cells. After the coelomic epithelial cells migrate into the gonad, there is first a decision to become interstitial or supporting cells, and then the transient expression of SRY in the latter determines their fate as Sertoli cells by up-regulating Sox9.
Alkaline Phosphatase↗