Important genes involved in the cascade of sex determination and differentiation of teleosts

Tạp chí Khoa học - Công nghệ Thủy sản Số 3/2013 174 • TRƯỜNG ĐẠI HỌC NHA TRANG IMPORTANT GENES INVOLVED IN THE CASCADE OF SEX DETERMINATION AND DIFFERENTIATION OF TELEOSTS MỘT SỐ GEN CHÍNH THAM GIA VÀO QUÁ TRÌNH KIỂM SOÁT VÀ BIỆT HÓA GIỚI TÍNH TRÊN CÁ XƯƠNG Srisupaph POONLAPHDECHA1 Ngày nhận bài: 15/7/2 013; Ngày phản biện thông qua: 06/9/2013; Ngày duyệt đăng: 10/9/2013 ABSTRACT Teleosts possess a variety of mechanisms for sex determination and differentiation. Sex steroids and temperature play an important role in the regulation of sex gonadal differentiation. Patterns of gene-initiated sexual differentiation are diverse, and species may or may not exhibit sexual dimorphic expression depending on spacing and timing of gene expression, organs, species and stage of fi sh. Several genes involved in sexual determination and differentiation pathways in vertebrates (particularly in mammals) have also been characterised in teleosts, such as amh, sox9, dmrt1, cyp19, foxl2, sf1, dax1 and igf1. Keywords: dpf, amh, sox9, dmrt1, cyp19, foxl2, sf1, dax1, igf1 TÓM TẮT Quá trình kiểm soát và biệt hóa giới tính ở cá xương được thực hiện bởi một cơ chế phức tạp, trong đó hormone sinh dục và nhiệt độ đóng vai trò quan trọng. Trên các loài cá khác nhau, cơ chế kiểm soát và biệt hóa giới tính tương đối đa dạng. Ngay cả trong cùng một loài, sự biệt hóa và biểu hiện thành kiểu hình giới tính ở cá cũng có thể khác nhau, tùy thuộc vào sự biểu hiện của các gen tại các cơ quan trong cơ thể ở các giai đoạn phát triển khác nhau. Nhiều gen tham gia vào quá trình kiểm soát và biệt hóa giới tính trên động vật có xương sống, đặc biệt là ở động vật có vú như: amh, sox9, dmrt1, cyp19, foxl2, sf1, dax1 and igf1. Vai trò của các gen này cũng đã được xác định và phân lập trên các xương. Từ khóa: dpf, amh, sox9, dmrt1, cyp19, foxl2, sf1, dax1, igf1 I. INTRODUCTION There are over 32,500 species of fi sh distributed in a large variety of habitats around the world [41]. Fish possess a large range of mechanisms for sexual determination and patterns of sexual differentiation; a matter of considerable sc ientifi c interest. Sex determination is consequent upon the sex-chromosome complement of the fi sh embryo: the presence of a Y chromosome results in formation of the testis, while its absence, and the presence of a second X chromosome, results in formation of an ovary. Following sex determination, hormones produced by the testis or ovary then stimulate tissue differentiation which are sex-specifi c. Several gene families involved in the sexual determination of other species of vertebrates have also been found in fi sh, suggesting a natural conservation of sexual determining pathways [10]. However, no equivalent to the mammalian Sry gene has been described in teleosts as yet, with the exception of dmy in medaka. As genomic studies evolve, it is becoming apparent that the master sex-determinants which govern the mechanisms of sex determination are not at all well conserved between phyla. Nevertheless, further ‘downstream’ conservation of the sex determination and differentiation cascade appears to be more in evidence. The knowledge base concerning molecular mechanisms of sex differentiation in mammals is advanced, but is less so in non-mammalian 1 Dr. Srisupaph POONLAPHDECHA: Department of Biology, Udon Thani Rajabhat University, Udon Thani, Thailand VAÁN ÑEÀ TRAO ÑOÅI Tạp chí Khoa học - Công nghệ Thủy sản Số 3/2013 TRƯỜNG ĐẠI HỌC NHA TRANG • 175 Fig 1: Mouse sexual development. AMH produced by the Sertoli cells of the foetal testes causes regression of the Müllerian ducts and testosterone (T) produced by Leydig cells induces differentiation of the Wolffi an duct system. The absence of both hormones during female foetal development permits the development of the Müllerian duct system while the Wolffi an ducts passively regress [4]. Amh is also found in fi sh but its role is not clear since, among fi sh, only ray-fi nned species such as sturgeons (Acipenser spp.) develop Müllerian ducts, and these ducts do not degenerate in males, as occurs in mammals [66]. Teleost fi sh do not possess Müllerian ducts, but do possess amh orthologs that show a sexually dimorphic expression during gonadal sex differentiation and/or adulthood, for example in Japanese eel (Anguilla japonica) [35], Japanese fl ounder (Paralichthys olivaceus) [70], zebrafi sh (Danio rerio) [51], sea bass (Dicentrarchus labrax) [20] and rainbow trout (Oncorhynchus mykiss) [3]. Northern hybridisation exhibited a single transcript only for amh in the testis in zebrafi sh [52], while Amh has been shown to be localised in the Sertoli cells of adult tissue in the species previously described. In adult fi sh, amh expression patterns also vary among the species. In medaka hatchlings there is no sexual dimorphic amh expression, whereas in adult testes it was detected in the somatic cells surrounding spermatogonia and spermatocysts [26]. On the other hand, in zebrafi sh juveniles, amh expression indicated a clear sexually dimorphic pattern. In contrast to juveniles, adults showed amh expression in both male and female gonads [51, 52]. Furthermore, amh in Japanese fl ounder gonads has a sexual dimorphic expression during sex differentiation which was detected only in the testis [70]. Tilapia amh begins to be expressed in undifferentiated gonads of both sexes, and is highly expressed in male, but not in female gonads [21, 46]. Moreover, amh levels decreased in the brain up to 10 dpf (days post fertilisation) before they were ‘up-regulated’ in differentiating testes [46]. In rainbow trout, amh expression was observed in the gonads of both sexes at 28 dpf. Nonetheless, amh was highly expressed and was found in male cells after 37 dpf and its expression was detected in somatic cells near germ cells [62], indicating that amh plays a role in testis differentiation. In addition, in pejerrey Odontesthes bonariensis, amh showed higher expression at masculinising (29°C) than at feminising (17°C) temperatures during the gonadal differentiation period [15]. vertebrates, particularly in fi sh. Several mammalian genes are conserved in non-mammalian vertebrates, although spatial and temporal differences suggest that some have different roles and regulative mechanisms [56]. In summary, this is a short review of the genes amh, sox9, dmrt1, cyp19a1b ETC) known to be involved in sex determination and differentiation pathways in teleosts. 1. Amh (Anti-Müllerian hormone) Amh, also known as Müllerian inhibiting substance (MIS), is a dimeric glycoprotein that inhibits the development of the Müllerian ducts in the male embryo and is secreted by the gonadal Sertoli cells is a distant member of the transforming growth factor-b (TGF β) family and acts via two receptors, type-I and type-II [11]. Amh is required for the regression of Müllerian (paramesonephric) ducts, which in its absence would normally develop into the Fallopian tubes, uterus, and upper vagina as is observed in female embryos (Fig.1) [37]. Amh blocks the differentiation of somatic precursor cells into mature Leydig cells and also affects ovarian functions by diverting the steroidogenic pathway from estrogens to androgens through inhibition of aromatase activity [61]. Tạp chí Khoa học - Công nghệ Thủy sản Số 3/2013 176 • TRƯỜNG ĐẠI HỌC NHA TRANG 2. Sox9 (Sex determining region Y)-box 9): autosomal sex reversal Sox9 is one of the important transcription factors in the development of many tissues and organs, particularly in chondrogenesis and sex determination. Sox9 codes for a putative transcription factor that also contains an HMG box, the DNA-binding motif. Sox9 acts in the testicular differentiation cascade in vertebrates. In mammals, Sox9 is a target of SRY (sex determining region Y) and is a critical gene for testis differentiation [12]. In the absence of Sox9a male to female sex reversal occurs [6]. In mammals, Sox9 regulates the expression of amh in the Sertoli cells of mice [68]. In teleosts, the sox9 gene has also been identifi ed in several species and, in the majority, two genes have been found which are considered to be orthologous to the sox9 of tetrapods. In zebrafi sh, Sox9a has been detected in the testis and other organs (brain, kidney, muscle) while sox9b was specifi c to the ovary [7]. Sox9 genes have been identifi ed in a number of teleost species: including rainbow trout [62], zebrafi sh [7, 63], medaka [69], guppy [54], Cyprinus carpio [13] and the eel Monopterus albus [71]. In these species, sox9 has been demonstrated to be related to some events in male sexual differentiation and may possibly play an important role in the process. 3. Dmrt1 (Doublesex- and mab-3 (DM)-related transcription factor1) Dmrt1 belongs to the DM domain gene family. Two genes which encoded proteins with a DNA-binding motif were identifi ed. They were conserved and homologous with doublesex (dsx) and mab-3 genes involved in sex development in Drosophila and Caenorhabditis, respectively. These similar regions were called the DM domain (after Dsx and mab-3). The DM-domain genes were the fi rst to reveal sexual dimorphism operating across both vertebrates and invertebrates [57]. Dmrt1 is conserved in structure and function in male sexual determination and differentiation in vertebrates. Deletion of a chromosome segment containing Dmrt1 results in sex reversal in humans [49]. In rainbow trout, dmrt1 is specifi cally expressed in male gonads and is involved in testicular sexual differentiation [62]. Similarly, in tilapia Oreochromis niloticus, dmrt1 was found to be highly expressed in the adult male gonads [18], but not at all expressed in female gonads [21]. Dmrt1 is involved in tilapia sex differentiation, being the fi rst gene to exhibit ‘up-regulation’ in the gonads of tilapia genetic males with XY genotype [21]. The critical role of dmrt1 in the testicular differentiation of this species was confi rmed by sexual reversion experiments performed with hormonal treatments. In XY fi sh treated with estrogens, dmrt1 is not expressed, whereas it is expressed in XX males [18, 27]. Recently, aromatase is one of the targets of dmrt1 which suppresses the female sex determination pathway by repressing aromatase gene transcription and estrogen production in the gonads of tilapia and possibly other vertebrates [65]. In medaka, the dmrt1 gene is autosomic and also affects testicular differentiation [28, 33]. In addition, a functional copy of this gene named dmy is found in the Y chromosome, and has been proposed as the sex determining gene of this species [32, 40]. In zebrafi sh, on the other hand, dmrt1 does not show a sexually dimorphic pattern of expression, being expressed after the undifferentiated gonadal stage in both sexes, which suggests that dmrt1 plays a role during gonad development in both males and females [19]. 4. Cyp19 (aromatase) In teleosts, aromatase is a duplicated gene, cyp19a1a ‘gonadal aromatase’ or ‘ovarian aromatase’ and cyp19a1b ‘neural aromatase’ or ‘brain aromatase.’ The cyp19a1a gene is mainly expressed in the differentiating and adult gonad (mainly the ovary) of teleost fi shes. The cyp19a1b gene is highly expressed in the teleost brain in both males and females [42], but sexually dimorphic brain expression during gonadal sexual differentiation has not been established [24]. Cyp19a1b was expressed during gonadal differentiation and was found to be expressed at low levels both in male and female gonads. Furthermore, in Nile tilapia and Japanese fugu the cyp19a1b gene was expressed within the early developing testis and was also induced following female-to-male androgen-induced sex change in tilapia and Japanese fugu (Takifugu rubipres) [58, 59, 48]. However, the implications of this early cyp19a1b expression in the differentiating testis remain unclear. Tạp chí Khoa học - Công nghệ Thủy sản Số 3/2013 TRƯỜNG ĐẠI HỌC NHA TRANG • 177 Fig 2: Temperature-dependent sex determination (TSD). Aromatase activity levels during the thermosensitive period (TSP: the temperature at which the eggs are incubated during the middle one-third of embryonic development) are regulated by the temperature of the environment and control gonadal differentiation [9, 30]. 5. Foxl2 (forkheadbox L2) Foxl2 is a putative winged helix/forkhead transcription factor gene and a sexually dimorphic marker of ovarian differentiation in vertebrates. It is also involved in ovarian functions in adult females. In the vertebrate differentiation of mammals, Foxl2 expression is conserved in the earliest stages of ovarian differentiation [3], birds [17] and reptiles, particularly in granulosa cell differentiation. Foxl2 possibly acts in correlated fashion with the Cyp19 gene [17]. Foxl2 also plays an important role in the ovarian differentiation of teleosts [29]. In tilapia and medaka, foxl2 expression is initially detected in the somatic cells surrounding germ cells in gonads that have initiated ovarian differentiation, and its expression is maintained in the granulosa cells accompanying ovarian development, mainly within pre-vitellogenic and vitellogenic follicles [38]. In the rainbow trout, two genes, foxl2a and foxl2b, have now been cloned. Foxl2 is also correlated with the transcriptional regulation of cyp19a1 in tilapia [64], rainbow trout [2], Japanese fl ounder [67] and medaka [39]. Cytochrome P450 aromatase (P450arom; Cyp19) is the steroidogenic enzyme responsible for the conversion of androgen to estrogen. In the Japanese fl ounder Paralichthys olivaceus, high temperatures suppress the expression of foxl2 and the receptor of follicle stimulating hormone fshr during early sexual differentiation. In this species, foxl2 has been shown in vitro to regulate the aromatase expression during sex differentiation [67]. In mammals, it has been shown that FSH stimulates estrogen biosynthesis by transcriptional regulation of the aromatase gene [16]. Heat stress has recently been shown to inhibit FSHR expression within the granulosa cells, resulting in a reduction of aromatase activity [55]. Heat stress may therefore suppress estrogen biosynthesis by inhibiting fshr transcript expression in the gonads of the XX female fl ounder during early sex differentiation and result in sex-reversal [67]. 6. Sf1 steroidogenic factor 1 (=nr5a1) Sf1 is an orphan nuclear receptor that regulates transcription of many genes during sex development in vertebrates. In mammals, sf1 expression is required for maintenance of the early gonad stages in both sexes and also in testis differentiation [43]. It has been shown that Sf1 co-activates SRY in the stimulation of Sox9 [53]. Sf1 is an important activator of steroidogenic enzymes in mammals [22] and has been shown to regulate aromatase [36]. In reptiles, sf1 expression increases at MPT and with aromatase inhibitory treatment [47]. It has been reported that the activity of the enzyme aromatase and the estrogens, as well assteroid receptors in both sexes, infl uences temperature-dependent sex determination (TSD) in reptiles [8, 45]. Aromatase expression is ‘down-regulated’ when larvae are incubated at masculinising temperatures in TSD-teleosts (Fig. 2) [25, 9]. In Odontesthes bonarensis, aromatase is involved in ovarian differentiation and is thought to be essential in the TSD mechanism of this species [14]. At female promoting temperatures (FPT) cyp19a1a is ‘up-regulated,’ whereas at male promoting temperatures (MPT) it is not expressed. Tạp chí Khoa học - Công nghệ Thủy sản Số 3/2013 178 • TRƯỜNG ĐẠI HỌC NHA TRANG In tilapia, sf1 is expressed within the gonads of both sexes at an early stage [64] but shows no sex differences in its expression. Levels increased later in ovaries from 14 to 29 dpf, later becoming higher in testis at 74 dpf [21], suggesting that sf1 is not a regulator of aromatase. 7. Dax1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region on chromosome X, gene 1): a potential ovary-determining gene on an autosome. The Dax1 gene is a member of the nuclear hormone receptor superfamily. Dax1 acts in part by repressing the transcription of other nuclear receptors, including steroidogenic factor 1 (SF1) and estrogen and androgen receptors [34]. Dax1 was initially thought to be a testis antagonist in mammals [60]. However, while not required for ovary development, it is required for development of the testis [34]. In fi sh, dax1 has been isolated and characterised in several species, including tilapia, rainbow trout, medaka and Dicentrarchus labrax, a member of the Moronidae family [3, 39]. In most of these species, its pattern of expression during gonadal development is understood, but its role during sexual determination is unclear. In rainbow trout, dax1 expression is known to rise in the developing testicle, suggesting its involvement in testicular differentiation [3]. In contrast, in tilapia, dax1 expression levels are higher in XX than in XY gonads. In this species, dax1 is thought to be involved in the regulation of sexual gonadal differentiation, inhibiting transcriptional activation of genes that code for steroidogenic enzymes, similarly as in mammals [21]. In D. labrax, dax1 seems to be important in gonadal development and differentiation, but not, apparently, for sexual determination [31]. In medaka, [39] were unable to identify mRNA of this gene during the sexual differentiation period, which suggests that dax1 does not play a crucial role in the process. In this species, dax1 expression was only detected in the ovary of adult fi sh where its action may be suppression of the aromatase enzyme. 8. Igf1 (Insulin-like growth factor 1) IGF-1 has a substantial involvement in the regulation of growth, tissue differentiation and reproduction by selectively promoting mitogenesis and differentiation and inhibiting apoptosis [50]. Igf1 mRNA and/or peptide have been shown to be present in rainbow trout, tilapia, and sea bass in spermatogonia, spermatocytes, Sertoli, and Leydig cells [5], suggesting autocrine / paracrine functions of igf1. Igf1 peptide and/or mRNA have also been localized in granulosa cells from the onset of their development in red sea bream [23], gilthead sea bream [44], and tilapia [5]. Igf1 in tilapia appears very early and is distributed distinctly in the gonads [5], suggesting that igf1 has a signifi cant local impact in the development of both male and female fi sh gonads. Igf1 mRNA and peptide appeared in somatic cells in the early gonad anlage of males and females from 7 to 9 dpf. At this stage, the gonad anlage is still undifferentiated; therefore, igf1 in the somatic cells may be of crucial importance to further gonad. Both IGF-I mRNA and peptide appeared in female germ cells at 29 dpf at the onset of fi rst ovarian meiosis [5]. In male germ cells they were each detected as late as 51–53 dpf, which coincides with the onset of testes meiosis. It was therefore suggested, that IGF-1 production in the germ cells is linked to the onset of meiosis that in tilapia. II. CONCLUSION The mechanisms of sex determination and patterns of gonadal differentiation in teleosts render them interesting models for investigating these mechanisms from the molecular, cellular, physiologic, phylogenetic and evolutionary perspectives. Currently, data in this fi eld have had great impact on the understanding of crucial reproductive aspects in vertebrates, such as sexual determination and differentiation. At present, new methodologies used for teleost research have led to the characterisation of several genes described in the sexual determination and differentiation pathways of other vertebrates. However, as no sex determining gene, which would be equivalent to Sry in mammals, has been found in non-mammalian vertebrates, autosomal genes may possibly fulfi ll this function. The discovery of dmy, the sex determining gene in medaka, presented the possibility of studying this gene in other fi sh. However, since it has Tạp chí Khoa học - Công nghệ Thủy sản Số 3/2013 TRƯỜNG ĐẠI HỌC NHA TRANG • 179 not been found in other species, variability in teleosts may be such that a universal sex determining gene may not exist within this group. In addition, sex may be determined by multiple mechanisms in vertebrates. 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