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Abstract Production of sperm and androgens is the main function of the testis. This depends on normal development of both testicular somatic cells and germ cells. A genetic program initiated from the Y chromosome gene sex-determining region Y (SRY) directs somatic cell specification to Sertoli cells that orchestrate further development. They first guide fetal germ cell differentiation toward spermatogenic destiny and then take care of the full service to spermatogenic cells during spermatogenesis. The number of Sertoli cells sets the limits of sperm production. Leydig cells secrete androgens that determine masculine development. Testis development does not depend on germ cells; that is, testicular somatic cells also develop in the absence of germ cells, and the testis can produce testosterone normally to induce full masculinization in these men. In contrast, spermatogenic cell development is totally dependent on somatic cells. We herein review germ cell differentiation from primordial germ cells to spermatogonia and development of the supporting somatic cells. Testicular descent to scrota is necessary for normal spermatogenesis, and cryptorchidism is the most common male birth defect. This is a mild form of a disorder of sex differentiation. Multiple genetic reasons for more severe forms of disorders of sex differentiation have been revealed during the last decades, and these are described along with the description of molecular regulation of testis development.

Sex in vertebrates is commonly determined by genotype and environmental conditions, such as temperature. A few species display intermediate systems, combining sex chromosomes with temperature effect. This phenomenon has been reported in gibel carp ( Carassius gibelio ), an invasive cyprinid fish whose invasiveness is linked to the combination of sexual and asexual reproduction. Here, we compared gonadal transcriptomes between genotypic males and temperature-induced males of C. gibelio , focusing specifically on genes related to reproduction. Many meiosis and male differentiation pathways were common to genotypic and temperature-induced males. However, the underrepresentation of reproduction- and spermatogenesis-related terms in temperature-induced males suggests reduced reproductive abilities. Our study further highlights differential regulation of key genes related to male differentiation, steroid hormone signalling, meiosis, spermatogenesis, flagellar function, and sperm-egg interaction. In particular, induced males strongly overexpressed the key sex differentiation regulator hsd17b2 and slightly overexpressed the meiotic gene mnd1 , while genotypic males overexpressed sox8a , cyp19a1a , and the crucial fertilization gene izumo . Our study highlights the importance of males in the transition from asexual to sexual reproduction in this species and contributes to understanding the molecular mechanisms underlying the reproductive plasticity and invasiveness of C. gibelio in Europe.

The sexual differentiation paradigm contends that the female pattern of the reproductive system is established by default because the male reproductive tracts (Wolffian ducts) in the female degenerate owing to a lack of androgen. Here, we discovered that female mouse embryos lacking Coup-tfII (chicken ovalbumin upstream promoter transcription factor II) in the Wolffian duct mesenchyme became intersex—possessing both female and male reproductive tracts. Retention of Wolffian ducts was not caused by ectopic androgen production or action. Instead, enhanced phosphorylated extracellular signal-regulated kinase signaling in Wolffian duct epithelium was responsible for the retention of male structures in an androgen-independent manner. We thus suggest that elimination of Wolffian ducts in female embryos is actively promoted by COUP-TFII, which suppresses a mesenchyme-epithelium cross-talk responsible for Wolffian duct maintenance.

Evolutionary novelties require rewiring of transcriptional networks and/or the evolution of new gene functions. Sex determination (SD), one of the most plastic evolutionary processes, requires such novelties. Studies on the evolution of vertebrate SD revealed that new master SD genes are generally recruited from genes involved in the downstream SD regulatory genetic network. Only a single exception to this rule is currently known in vertebrates: the intriguing case of the salmonid master SD gene (sdY), which arose from duplication of an immune-related gene. This exception immediately posed the question of how a gene outside from the classical sex differentiation cascade could acquire its function as a male SD gene. Here we show that SdY became integrated in the classical vertebrate sex differentiation cascade by interacting with the Forkhead box domain of the female-determining transcription factor, Foxl2. In the presence of Foxl2, SdY is translocated to the nucleus where the SdY:Foxl2 complex prevents activation of the aromatase (cyp19a1a) promoter in cooperation with Nr5a1 (Sf1). Hence, by blocking a positive loop of regulation needed for the synthesis of estrogens in the early differentiating gonad, SdY disrupts a preset female differentiation pathway, consequently allowing testicular differentiation to proceed. These results also suggest that the evolution of unusual vertebrate master sex determination genes recruited from outside the classical pathway like sdY is strongly constrained by their ability to interact with the canonical gonadal differentiation pathway.

Malaria-causing parasites ( Plasmodium ) have complex life histories in the tissues of humans. For the most part, the parasites focus their efforts on replication within the human host cells. However, occasionally, some replicating cells release gametes into the bloodstream, which are picked up by biting mosquitoes. Filarsky et al. discovered that the Plasmodium parasite keeps the production of gametes under tight epigenetic control using heterochromatin protein 1 (HP1). Plasmodium gametocytogenesis is initiated when HP1 is evicted from upstream of gamete-specific genes by gametocyte development 1 (GDV1) protein. GDV1 is in turn regulated by its antisense RNA. What triggers GDV1 expression remains unclear. Elucidating this pathway could provide a target for interrupting malaria transmission. Science , this issue p. 1259 Plasmodium replication is interrupted for gamete production by eviction of a heterochromatin binding protein upstream of the relevant genes. Malaria is caused by Plasmodium parasites that proliferate in the bloodstream. During each replication cycle, some parasites differentiate into gametocytes, the only forms able to infect the mosquito vector and transmit malaria. Sexual commitment is triggered by activation of AP2-G, the master transcriptional regulator of gametocytogenesis. Heterochromatin protein 1 (HP1)–dependent silencing of ap2-g prevents sexual conversion in proliferating parasites. In this study, we identified Plasmodium falciparum gametocyte development 1 (GDV1) as an upstream activator of sexual commitment. We found that GDV1 targeted heterochromatin and triggered HP1 eviction, thus derepressing ap2-g . Expression of GDV1 was responsive to environmental triggers of sexual conversion and controlled via a gdv1 antisense RNA. Hence, GDV1 appears to act as an effector protein that induces sexual differentiation by antagonizing HP1-dependent gene silencing.

Background The American alligator ( Alligator mississippiensis ) displays temperature-dependent sex determination (TSD), in which incubation temperature during embryonic development determines the sexual fate of the individual. However, the molecular mechanisms governing this process remain a mystery, including the influence of initial environmental temperature on the comprehensive gonadal gene expression patterns occurring during TSD. Results Our characterization of transcriptomes during alligator TSD allowed us to identify novel candidate genes involved in TSD initiation. High-throughput RNA sequencing (RNA-seq) was performed on gonads collected from A. mississippiensis embryos incubated at both a male and a female producing temperature (33.5 °C and 30 °C, respectively) in a time series during sexual development. RNA-seq yielded 375.2 million paired-end reads, which were mapped and assembled, and used to characterize differential gene expression. Changes in the transcriptome occurring as a function of both development and sexual differentiation were extensively profiled. Forty-one differentially expressed genes were detected in response to incubation at male producing temperature, and included genes such as Wnt signaling factor WNT11, histone demethylase KDM6B , and transcription factor C/EBPA . Furthermore, comparative analysis of development- and sex-dependent differential gene expression revealed 230 candidate genes involved in alligator sex determination and differentiation, and early details of the suspected male-fate commitment were profiled. We also discovered sexually dimorphic expression of uncharacterized ncRNAs and other novel elements, such as unique expression patterns of HEMGN and ARX . Twenty-five of the differentially expressed genes identified in our analysis were putative transcriptional regulators, among which were MYBL2, MYCL, and HOXC10, in addition to conventional sex differentiation genes such as SOX9 , and FOXL2. Inferred gene regulatory network was constructed, and the gene-gene and temperature-gene interactions were predicted. Conclusions Gonadal global gene expression kinetics during sex determination has been extensively profiled for the first time in a TSD species. These findings provide insights into the genetic framework underlying TSD, and expand our current understanding of the developmental fate pathways during vertebrate sex determination.

Sex chromosomes underlie the development of male or female sex organs across species. While systemic signals derived from sex organs prominently contribute to sex-linked differences, it is unclear whether the intrinsic presence of sex chromosomes in somatic tissues has a specific function. Here, we use genetic tools to show that cellular sex is crucial for sexual differentiation throughout the body in Drosophila melanogaster . We reveal that every somatic cell converts the intrinsic presence of sex chromosomes into the active production of a sex determinant, a female specific serine- and arginine-rich (SR) splicing factor. This discovery dismisses the mosaic model which posits that only a subset of cells has the potential to sexually differentiate. Using cell-specific sex reversals, we show that this prevalence of cellular sex drives sex differences in organ size and body weight and is essential for fecundity. These findings demonstrate that cellular sex drives differentiation programs at an organismal scale and highlight the importance of cellular sex pathways in sex trait evolution. While hormonal signals derived from sex organs are seen as the main contributors to sex differences, the global role of cellular sex remains poorly understood. Here, the authors show that every cell converts the intrinsic presence of sex chromosomes into the active production of a sex determinant.

Recent evidence challenged the traditional, categorical approach to sex differences, indicating that each human brain comprises a mosaic of features, some of which are more common among males, others, among females, whereas the remaining are equally common between sexes. Thus, a focus on regional sexual differentiation of brain function, instead of holistic sex-based categorization, could be more useful for understanding psychiatric conditions, such as mood and behavioural disorders, to which males and females are differentially vulnerable. To probe this untested hypothesis, we estimate sexual differentiation within each brain in a longitudinal ( N  = 199) and cross-sectional ( N  = 277) sample of male and female adolescents. Greater feminization of association networks, involved in higher-order cognition, compared to sensory networks, at ages 9-10 correlates with earlier puberty and greater immune/metabolic dysregulation at ages 11-12, particularly among girls. Greater masculinization of association networks relates to later puberty and reduced immune/metabolic dysregulation, especially among boys. The brain and physiological profiles sequentially mediate the relationship between genetic risk and rising mood/behavioural symptoms. These links are replicated in the cross-sectional sample and shown to hold across sexes. Our study emphasizes the importance of integrating assessments of regional sexual differentiation and physiology in personalizing psychiatric intervention in adolescence. Sexual differentiation in brain function along a sensory to-higher-order cognition axis is related to physiological aging and distinguishes between adolescent risk for mood vs behavioral problems, both longitudinally and cross-sectionally.

Background In the animal kingdom, mollusca is an important phylum of the Lophotrochozoa. However, few studies have investigated the molecular cascade of sex determination/early gonadal differentiation within this phylum. The oyster Crassostrea gigas is a sequential irregular hermaphrodite mollusc of economic, physiological and phylogenetic importance. Although some studies identified genes of its sex-determining/−differentiating pathway, this particular topic remains to be further deepened, in particular with regard to the expression patterns. Indeed, these patterns need to cover the entire period of sex lability and have to be associated to future sex phenotypes, usually impossible to establish in this sequential hermaphrodite. This is why we performed a gonadal RNA-Seq analysis of diploid male and female oysters that have not changed sex for 4 years, sampled during the entire time-window of sex determination/early sex differentiation (stages 0 and 3 of the gametogenetic cycle). This individual long-term monitoring gave us the opportunity to explain the molecular expression patterns in the light of the most statistically likely future sex of each oyster. Results The differential gene expression analysis of gonadal transcriptomes revealed that 9723 genes were differentially expressed between gametogenetic stages, and 141 between sexes (98 and 43 genes highly expressed in females and males, respectively). Eighty-four genes were both stage- and sex-specific, 57 of them being highly expressed at the time of sex determination/early sex differentiation. These 4 novel genes including Trophoblast glycoprotein-like, Protein PML-like, Protein singed-like and PREDICTED: paramyosin, while being supported by RT-qPCR, displayed sexually dimorphic gene expression patterns. Conclusions This gonadal transcriptome analysis, the first one associated with sex phenotypes in C. gigas , revealed 57 genes highly expressed in stage 0 or 3 of gametogenesis and which could be linked to the future sex of the individuals. While further study will be needed to suggest a role for these factors, some could certainly be original potential actors involved in sex determination/early sex differentiation, like paramyosin and could be used to predict the future sex of oysters.

Most cultured Japanese eels (Anguilla japonica) show male sex differentiation; however, natural gonadal sex differentiation has not been evaluated. In this study, this process was characterized in wild eels. Differentiated ovaries and testes were observed after the eels grew to 320 and 300 mm in total length, respectively. The youngest ovary and testis appeared at 3 and 4 years old, respectively; however, undifferentiated gonads were found up to 7 years, suggesting that sex differentiation was triggered by growth rather than aging. gsdf, amh, foxl2b and foxl3b were highly expressed in the testes, whereas figla, sox3, foxn5, zar1, and zp3 were highly expressed in the ovaries. The expression of cyp19a1a and foxl2a did not differ significantly between the testis and ovary. In the ovaries, the cyp19a1a and foxl2a levels were highest in the early stages, suggesting that their function is limited to early ovarian differentiation. The foxn5, zar1 and zp3 levels tended to increase in the later stages, suggesting that they function after the initiation of ovarian differentiation. In undifferentiated gonads, dimorphic gene expression was not observed, suggesting that the molecular sex differentiation phase is short and difficult to detect. These findings provide the first demonstration of the whole course of natural gonadal sex differentiation in eels at molecular and morphological levels.