Zebrafish sex determination and differentiation: Involvement of FTZ-F1 genes

Sex determination is the process deciding the sex of a developing embryo. This is usually determined genetically; however it is a delicate process, which in many cases can be influenced by environmental factors. The mechanisms controlling zebrafish sex determination and differentiation are not known. To date no sex linked genes have been identified in zebrafish and no sex chromosomes have been identified. However, a number of genes, as presented here, have been linked to the process of sex determination or differentiation in zebrafish. The zebrafish FTZ-F1 genes are of central interest as they are involved in regulating interrenal development and thereby steroid biosynthesis, as well as that they show expression patterns congruent with reproductive tissue differentiation and function. Zebrafish can be sex reversed by exposure to estrogens, suggesting that the estrogen levels are crucial during sex differentiation. The Cyp19 gene product aromatase converts testosterone into 17 beta-estradiol, and when inhibited leads to male to female sex reversal. FTZ-F1 genes are strongly linked to steroid biosynthesis and the regulatory region of Cyp19 contains binding sites for FTZ-F1 genes, further linking FTZ-F1 to this process. The role of FTZ-F1 and other candidates for zebrafish sex determination and differentiation is in focus of this review.     

Primary events in C. elegans sex determination and dosage compensation

An outline of the complex regulatory gene network that controls all aspects of sexual dimorphism in the nematode C. elegans is now known in considerable details. This review describes the genes and gene interactions involved in the coordinate control of sex determination and X chromosome dosage compensation in C. elegans.     

Z and W chromosomes of chickens: studies on their gene functions in sex determination and sex differentiation

Since the discovery of SRY/SRY as a testis-determining gene on the mammalian Y chromosome in 1990, extensive studies have been carried out on the immediate target of SRY/SRY and genes functioning in the course of testis development. Comparative studies in non-mammalian vertebrates including birds have failed to find a gene equivalent to SRY/SRY, whereas they have suggested that most of the downstream factors found in mammals including SOX9 are also involved in the process of gonadal differentiation. Although a gene whose function is to trigger the cascade of gene expression toward gonadal differentiation has not been identified yet on either W or Z chromosomes of birds, a few interesting genes have been found recently on the sex chromosomes of chickens and their possible roles in sex determination or sex differentiation are being investigated. It is the purpose of this review to summarize the present knowledge of these sex chromosome-linked genes in chickens and to give perspectives and point out questions concerning the mechanisms of avian sex determination.     

Germ-line sex determination in Drosophila melanogaster

In Drosophila melanogaster, the mechanism of sex determination is substantially different in the germ line and in the soma. In the germ line, the process is not completely cell-autonomous, but requires some signals from the soma. Only some of the genes involved in somatic sex determination are also needed for germ cell development. Recent genetic studies have identified loci required for germ-line sex determination.     

Temperature-dependent sex determination in the American alligator: expression of SF1, WT1 and DAX1 during gonadogenesis

Sex determination in mammals and birds is chromosomal, while in many reptiles sex determination is temperature dependent. Morphological development of the gonads in these systems is conserved, suggesting that many of the genes involved in gonad development are also conserved. The genes SF1, WT1 and DAX1 play various roles in the mammalian testis-determining pathway. SF1 and WT1 are thought to interact to cause male-specific gene expression during testis development, while DAX1 is believed to inhibit this male-specific gene expression. We have cloned SF1 and DAX1 from the American alligator, a species with temperature-dependent sex determination (TSD). SF1, DAX1 and WT1 are expressed in the urogenital system/gonad throughout the period of alligator gonadogenesis which is temperature sensitive. SF1 appears to be expressed at a higher level in females than in males. This SF1 expression pattern is concordant with the observed pattern during chicken gonadogenesis, but opposite to that observed during mouse gonadogenesis. Although the observed sexual dimorphism of gonadal SF1 expression in alligators and chickens is opposite that observed in the mouse, it is probable that SF1 is involved in control of gonadal steroidogenesis in all these vertebrates. DAX1 and WT1 are both expressed during stages 22-25 of both males and females. However, there appear to be no sex differences in the expression patterns of these genes. We conclude that DAX1, WT1 and SF1 may be involved in gonadal development of the alligator. These genes may form part of a gonadal-development pathway which has been conserved through vertebrate evolution.     

Balancing sex chromosome expression and satisfying the sexes

Equalizing sex chromosome expression between the sexes when they have largely differing gene content appears to be necessary, and across species, is accomplished in a variety of ways. Even in birds, where the process is less than complete, a mechanism to reduce the difference in gene dose between the sexes exists. In early development, while the dosage difference is unregulated and still in flux, it is frequently exploited by sex determination mechanisms. The Drosophila female sex determination process is one clear example, determining the sexes based on X chromosome dose. Recent data show that in Drosophila, the female sex not only reads this gene balance difference, but at the same time usurps the moment. Taking advantage of the transient default state of male dosage compensation, the sex determination master-switch Sex-lethal which resides on the X, has its expression levels enhanced before it works to correct the gene imbalance. Intriguingly, key developmental genes which could create developmental havoc if their levels were unbalanced show more exquisite regulation, suggesting nature distinguishes them and ensures their expression is kept in the desirable range.     

植物性别决定的研究进展

通过回顾近年来以多种植物为材料进行的性染色体观察,性别决定基因及调控方式的研究,对植物性别决定的机制进行了初步探讨,从而可以看出不同植物具有不同的性别决定机制：对于有性染色体的植物而言,目前已经从Y染色体上分离和鉴定了许多与雄性发育紧密相关的基因;部分性别决定基因和调控序列已利用构建减法文库,诱导突变体等方法从一些植物中获得。此外,还有研究表明,DNA脱甲基化,以及某些激素(如赤霉素、乙烯、Ace)都对植物的性别决定有重要作用。     

Sex as a response to oxidative stress: stress genes co-opted for sex

Despite a great deal of interest, the evolutionary origins and roles of sex remain unclear. Recently, we showed that in the multicellular green alga, Volvox carteri, sex is a response to increased levels of reactive oxygen species (ROS), which could be indicative of the ancestral role of sex as an adaptive response to stress-induced ROS. To provide additional support for the suggestion that sex evolved as a response to oxidative stress, this study addresses the hypothesis that genes involved in sexual induction are evolutionarily related to genes associated with various stress responses. In particular, this study investigates the evolutionary history of genes specific to the sexual induction process in V. carteri--including those encoding the sexual inducer (SI) and several SI-induced extracellular matrix (ECM) proteins. Surprisingly, (i) a highly diversified multigene family with similarity to the V. carteri SI and SI-induced pherophorin family is present in its unicellular relative, Chlamydomonas reinhardtii (which lacks both a SI and an ECM) and (ii) at least half of the 12 identified gene members are induced (as inferred from reported expressed sequence tags) under various stress conditions. These findings suggest an evolutionary connection between sex and stress at the gene level, via duplication and/or co-option.     

X chromosome dosage compensation and its relationship to sex determination in C. elegans

A genetic regulatory hierarchy controls all aspects of Caenorhabditis elegans sex determination and X chromosome dosage compensation in response to the primary sex-determining signal, the X/A ratio. Initially, these two processes are coordinately regulated by a group of genes that transmit this primary signal to downstream genes that preferentially control either sex determination or dosage compensation. The relationship between these two processes is complex: not only are they coordinately controlled, a feedback mechanism operates to allow a disruption in dosage compensation to affect sexual fate. We describe our genetic and molecular understanding of the regulatory hierarchy, the feedback control and the dosage compensation process itself.     

Some inconvenient truths about sex chromosome dosage compensation and the potential role of sexual conflict

Sex chromosome dosage compensation was once thought to be required to balance gene expression levels between sex-linked and autosomal genes in the heterogametic sex. Recent evidence from a range of animals has indicated that although sex chromosome dosage compensation exists in some clades, it is far from a necessary companion to sex chromosome evolution, and is in fact rather rare in animals. This raises questions about why complex dosage compensation mechanisms arise in some clades when they are not strictly needed, and suggests that the role of sex-specific selection in sex chromosome gene regulation should be reassessed. We show there exists a tremendous diversity in the mechanisms that regulate gene dosage and argue that sexual conflict may be an overlooked agent responsible for some of the variation seen in sex chromosome gene dose regulation.     

In search of determinants: gene expression during gonadal sex differentiation

The diversity of inputs that guide sexual fate during development is both intriguing and daunting. In the field of fish biology, the study of sex determination is of great importance. For example, in aquaculture, sexually dimorphic growth rates and overall size leads to one sex being more marketable than the other. Moreover, for breeding purposes it is important to maintain balanced sex ratios. Furthermore, sex determination is sensitive to environmental factors, such as temperature and contaminants, which can lead to skewed sex ratios, intersexes and sterility in wild or farmed fish. The gonad is typically the first organ to exhibit morphological signs of sexual dimorphism and therefore is likely to be the primary organ system whose fate is controlled by the sex determination cues in many fish species. Additionally, the sexual fate of the gonad has been shown to fully or partially control organismal sex differentiation. Thus, understanding the genetic regulation of gonadal sex differentiation is critical in studies of fish sex determination. This review summarizes recent knowledge of genes expressed during gonadal sex differentiation in gonochoristic teleost fish. Three species are discussed, which serve as excellent model systems for probing teleost sex differentiation: the Oreochromis niloticus, Oryzias latipes and Danio rerio. The similarities and differences between gonadal gene expression in these three species and in comparison to mammals suggest conserved roles during vertebrate gonadal sex differentiation. In the future, it will be essential to develop tools to assay the function of genes expressed during gonadal sex differentiation in fish.     

Meta-analysis of sex differences in gene expression in schizophrenia

Schizophrenia is a severe psychiatric disorder which influences around 1 % of the worldwide population. Differences between male and female patients with schizophrenia have been noted. There is an earlier age of onset in males compared with females with this diagnosis, and in addition, there are differences in symptom profiles between the sexes. The underlying molecular mechanism of sex difference remains unclear. Here we present a comprehensive analysis to reveal the sex differences in gene expression in schizophrenia with stringent statistics criteria. We compiled a data set consisting of 89 male controls, 90 male schizophrenia patients, 35 female controls and 32 female schizophrenia patients from six independent studies of the prefrontal cortex (PFC) in postmortem brain. When we tested for a sex by diagnosis interaction on gene expression, 23 genes were up-regulated and 23 genes were down-regulated in the male group (q-value?<?0.05), several genes are related to energy metabolism, while 4 genes are located on sex chromosome. No genes were statistically significant in the female group when multiple testing correction were conducted (q-value <0.05), most likely due to the small sample size. Our protocol and results from the male group provide a starting point for identifying the underlying different mechanism between male and female schizophrenia patients.     

Bird sex determination

During the evolution, sex determination occurred early. Sex determining factors were progressively isolated from other genes in sexual chromosomes, or gonosomes. Among vertebrates, evolution took two opposite pathways : in mammals, the system of XX:XY sex determination, with Y chromosome, induces male differentiation. In contrast, in birds, the system ZZ:ZW, with the W chromosome, induces female differentiation. But comparative studies show that the two pathways are not so simple. In the chicken as in the lower vertebrates, estrogens play a central role in gonadal sex differentiation. Several genes, show to be critical for mammalian determination, are also expressed in the chicken but their expression pattern differs, indicating functional plasticity. The W-linked female determinants remains still unknown. But comparative studies of the two pathways, with conserved and divergent elements, are broadening our understanding of sex determination.     

Chromatin landscape associated with sexual differentiation in a UV sex determination system

In many eukaryotes, such as dioicous mosses and many algae, sex is determined by UV sex chromosomes and is expressed during the haploid phase of the life cycle. In these species, the male and female developmental programs are initiated by the presence of the U- or V-specific regions of the sex chromosomes but, as in XY and ZW systems, sexual differentiation is largely driven by autosomal sex-biased gene expression. The mechanisms underlying the regulation of sex-biased expression of genes during sexual differentiation remain elusive. Here, we investigated the extent and nature of epigenomic changes associated with UV sexual differentiation in the brown alga Ectocarpus, a model UV system. Six histone modifications were quantified in near-isogenic lines, leading to the identification of 16 chromatin signatures across the genome. Chromatin signatures correlated with levels of gene expression and histone PTMs changes in males versus females occurred preferentially at genes involved in sex-specific pathways. Despite the absence of chromosome scale dosage compensation and the fact that UV sex chromosomes recombine across most of their length, the chromatin landscape of these chromosomes was remarkably different to that of autosomes. Hotspots of evolutionary young genes in the pseudoautosomal regions appear to drive the exceptional chromatin features of UV sex chromosomes.     

Sex inversion as a model for the study of sex determination in vertebrates

As a consequence of genetic sex determination, the indifferent gonadal blastema normally becomes either a testis or an ovary. This applies to mammals and to the majority of non-mammalian vertebrates. With the exception of placental mammals, however, partial or complete sex inversion can be induced in one sex by sexual steroid hormones of the opposite sex during a sensitive period of gonadogenesis. There is evidence that also during normal gonadogenesis in these species, in the XY/XX mechanism of sex determination testicular differentiation is induced by androgens, and in the ZZ/ZW mechanism, ovarian differentiation by oestrogens. In either case, the hormones may act via serological H-Y antigen as a morphogenetic factor. In contrast, in placental mammals including man, primary gonadal differentiation is independent of sexual steroid hormones, and factors directing differential gonadal development have not yet been conclusively identified. However, various mutations at the chromosome or gene level, resulting respectively in sex inversion or intersexuality, have provided clues as to some genes involved and their possible nature. In this context also, serological H-Y antigen is discussed as a possible factor acting on primordial gonadal cells and inducing differential growth or morphogenesis or both. The data available at present allow a tentative outline of the genetics of sex determination in placental mammals.     

Multiple molecular approaches yield no evidence for sex‐determining genes in lake sturgeon (Acipenser fulvescens)

Common DNA‐based sexing assays have been widely used for the conservation and management of mammals and birds. However, many fishes do not have genetic sex determination and in those that do, the plasticity of the genes involved means that species‐specific assays are normally required. Such DNA‐sexing markers would be especially valuable in lake sturgeon (Acipenser fulvescens) because of their sexual monomorphism, delayed sexual maturity, and conservation status. We tried to identify genetic differences between male and female lake sturgeon using several different molecular genetic methods, including randomly amplified polymorphic DNA, representational difference analyses, subtractive hybridization, and a candidate gene approach. Ultimately, a number of genes were identified but none was sex‐specific. Although the ultimate mechanism of sex determination is yet unknown, it is possible that sex determination is environmental in lake sturgeon, especially since recent studies have also failed to identify sex determination genes in other sturgeon species.