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Physiological Reviews Jul 2021A diverse array of sex determination () mechanisms, encompassing environmental to genetic, have been found to exist among vertebrates, covering a spectrum from fixed... (Review)
Review
A diverse array of sex determination () mechanisms, encompassing environmental to genetic, have been found to exist among vertebrates, covering a spectrum from fixed mechanisms (mammals) to functional sex change in fishes (sequential hermaphroditic fishes). A major landmark in vertebrate was the discovery of the gene in 1990. Since that time, many attempts to clone an ortholog from nonmammalian vertebrates remained unsuccessful, until 2002, when was discovered as the gene of a small fish, medaka. Surprisingly, however, was found in only 2 species among more than 20 species of medaka, suggesting a large diversity of genes among vertebrates. Considerable progress has been made over the last 3 decades, such that it is now possible to formulate reasonable paradigms of how and gonadal sex differentiation may work in some model vertebrate species. This review outlines our current understanding of vertebrate and gonadal sex differentiation, with a focus on the molecular and cellular mechanisms involved. An impressive number of genes and factors have been discovered that play important roles in testicular and ovarian differentiation. An antagonism between the male and female pathway genes exists in gonads during both sex differentiation and, surprisingly, even as adults, suggesting that, in addition to sex-changing fishes, gonochoristic vertebrates including mice maintain some degree of gonadal sexual plasticity into adulthood. Importantly, a review of various mechanisms among vertebrates suggests that this is the ideal biological event that can make us understand the evolutionary conundrums underlying speciation and species diversity.
Topics: Animals; Female; Gonads; Male; Sex Determination Processes; Sex Differentiation; Vertebrates
PubMed: 33180655
DOI: 10.1152/physrev.00044.2019 -
Journal of Neuroendocrinology Jul 2018Sexual identity and sexual orientation are independent components of a person's sexual identity. These dimensions are most often in harmony with each other and with an... (Review)
Review
Sexual identity and sexual orientation are independent components of a person's sexual identity. These dimensions are most often in harmony with each other and with an individual's genital sex, although not always. The present review discusses the relationship of sexual identity and sexual orientation to prenatal factors that act to shape the development of the brain and the expression of sexual behaviours in animals and humans. One major influence discussed relates to organisational effects that the early hormone environment exerts on both gender identity and sexual orientation. Evidence that gender identity and sexual orientation are masculinised by prenatal exposure to testosterone and feminised in it absence is drawn from basic research in animals, correlations of biometric indices of androgen exposure and studies of clinical conditions associated with disorders in sexual development. There are, however, important exceptions to this theory that have yet to be resolved. Family and twin studies indicate that genes play a role, although no specific candidate genes have been identified. Evidence that relates to the number of older brothers implicates maternal immune responses as a contributing factor for male sexual orientation. It remains speculative how these influences might relate to each other and interact with postnatal socialisation. Nonetheless, despite the many challenges to research in this area, existing empirical evidence makes it clear that there is a significant biological contribution to the development of an individual's sexual identity and sexual orientation.
Topics: Animals; Brain; Female; Gender Identity; Humans; Male; Sex Differentiation; Sexual Partners; Sexuality
PubMed: 29211317
DOI: 10.1111/jne.12562 -
International Journal of Molecular... Mar 2020The complex process of sexual differentiation is known to be influenced by biological and environmental determinants. The present review has the aim of summarizing the... (Review)
Review
The complex process of sexual differentiation is known to be influenced by biological and environmental determinants. The present review has the aim of summarizing the most relevant studies on the biological basis of sexual development, and in particular, it focuses on the impact of sex hormones and genetic background on the development of sexual differentiation and gender identity. The authors conducted a search of published studies on Medline (from January 1948 to December 2019). The evidence suggests that the sexual dimorphic brain could be the anatomical substrate of psychosexual development, on which gonadal hormones may have a shaping role during prenatal and pubertal periods. Additionally, according to several heritability studies, genetic components may have a role, but a promising candidate gene has not been identified. Even though growing evidence underlines the primary role of biological factors on psychosexual development, further studies are necessary to better explain their complex interactions.
Topics: Brain; Female; Gender Identity; Gene Expression Regulation; Hormones; Humans; Male; Sex Characteristics; Sex Differentiation; Sex Factors
PubMed: 32204531
DOI: 10.3390/ijms21062123 -
Endocrinology Oct 2020Gonadal hormones contribute to the sexual differentiation of brain and behavior throughout the lifespan, from initial neural patterning to "activation" of adult... (Review)
Review
Gonadal hormones contribute to the sexual differentiation of brain and behavior throughout the lifespan, from initial neural patterning to "activation" of adult circuits. Sexual behavior is an ideal system in which to investigate the mechanisms underlying hormonal activation of neural circuits. Sexual behavior is a hormonally regulated, innate social behavior found across species. Although both sexes seek out and engage in sexual behavior, the specific actions involved in mating are sexually dimorphic. Thus, the neural circuits mediating sexual motivation and behavior in males and females are overlapping yet distinct. Furthermore, sexual behavior is strongly dependent on circulating gonadal hormones in both sexes. There has been significant recent progress on elucidating how gonadal hormones modulate physiological properties within sexual behavior circuits with consequences for behavior. Therefore, in this mini-review we review the neural circuits of male and female sexual motivation and behavior, from initial sensory detection of pheromones to the extended amygdala and on to medial hypothalamic nuclei and reward systems. We also discuss how gonadal hormones impact the physiology and functioning of each node within these circuits. By better understanding the myriad of ways in which gonadal hormones impact sexual behavior circuits, we can gain a richer and more complete appreciation for the neural substrates of complex behavior.
Topics: Adult; Animals; Brain; Female; Hormones; Humans; Male; Nerve Net; Sex Characteristics; Sex Differentiation; Sexual Behavior; Sexual Behavior, Animal
PubMed: 32845294
DOI: 10.1210/endocr/bqaa150 -
Single-cell transcriptome reveals insights into the development and function of the zebrafish ovary.ELife May 2022Zebrafish are an established research organism that has made many contributions to our understanding of vertebrate tissue and organ development, yet there are still...
Zebrafish are an established research organism that has made many contributions to our understanding of vertebrate tissue and organ development, yet there are still significant gaps in our understanding of the genes that regulate gonad development, sex, and reproduction. Unlike the development of many organs, such as the brain and heart that form during the first few days of development, zebrafish gonads do not begin to form until the larval stage (≥5 days post-fertilization). Thus, forward genetic screens have identified very few genes required for gonad development. In addition, bulk RNA-sequencing studies that identify genes expressed in the gonads do not have the resolution necessary to define minor cell populations that may play significant roles in the development and function of these organs. To overcome these limitations, we have used single-cell RNA sequencing to determine the transcriptomes of cells isolated from juvenile zebrafish ovaries. This resulted in the profiles of 10,658 germ cells and 14,431 somatic cells. Our germ cell data represents all developmental stages from germline stem cells to early meiotic oocytes. Our somatic cell data represents all known somatic cell types, including follicle cells, theca cells, and ovarian stromal cells. Further analysis revealed an unexpected number of cell subpopulations within these broadly defined cell types. To further define their functional significance, we determined the location of these cell subpopulations within the ovary. Finally, we used gene knockout experiments to determine the roles of and for oocyte development and sex determination and/or differentiation, respectively. Our results reveal novel insights into zebrafish ovarian development and function, and the transcriptome profiles will provide a valuable resource for future studies.
Topics: Animals; Female; Gonads; Ovary; Sex Differentiation; Transcriptome; Zebrafish
PubMed: 35588359
DOI: 10.7554/eLife.76014 -
Cellular and Molecular Life Sciences :... Dec 2021Zebrafish have emerged as a major model organism to study vertebrate reproduction due to their high fecundity and external development of eggs and embryos. The... (Review)
Review
Zebrafish have emerged as a major model organism to study vertebrate reproduction due to their high fecundity and external development of eggs and embryos. The mechanisms through which zebrafish determine their sex have come under extensive investigation, as they lack a definite sex-determining chromosome and appear to have a highly complex method of sex determination. Single-gene mutagenesis has been employed to isolate the function of genes that determine zebrafish sex and regulate sex-specific differentiation, and to explore the interactions of genes that promote female or male sexual fate. In this review, we focus on recent advances in understanding of the mechanisms, including genetic and environmental factors, governing zebrafish sex development with comparisons to gene functions in other species to highlight conserved and potentially species-specific mechanisms for specifying and maintaining sexual fate.
Topics: Animals; Female; Germ Cells; Male; Protein Processing, Post-Translational; RNA; Sex Determination Processes; Sex Differentiation; Zebrafish
PubMed: 34936027
DOI: 10.1007/s00018-021-04066-4 -
Frontiers in Neuroendocrinology Jan 2019Sex plays a role in the incidence and outcome of neurological illnesses, also influencing the response to treatments. Despite sexual differentiation of the brain has... (Review)
Review
Sex plays a role in the incidence and outcome of neurological illnesses, also influencing the response to treatments. Despite sexual differentiation of the brain has been extensively investigated, the study of sex differences in microglia, the brain's resident immune cells, has been largely neglected until recently. To fulfill this gap, our laboratory developed several tools, including cellular and animal models, which bolstered in-depth studies on sexual differentiation of microglia and its impact on brain physiology, as well as on the onset and progression of neurological disorders. Here, we summarize the current status of knowledge on the sex-dependent function of microglia, and report recent evidence linking these cells to the sexual bias in the susceptibility to neurological brain diseases.
Topics: Animals; Brain; Brain Diseases; Humans; Microglia; Sex Characteristics; Sex Differentiation
PubMed: 30481522
DOI: 10.1016/j.yfrne.2018.11.003 -
Sexual Development : Genetics,... 2021Animals determine their sex genetically (GSD: genetic sex determination) and/or environmentally (ESD: environmental sex determination). Medaka (Oryzias latipes) employ a... (Review)
Review
Animals determine their sex genetically (GSD: genetic sex determination) and/or environmentally (ESD: environmental sex determination). Medaka (Oryzias latipes) employ a XX/XY GSD system, however, they display female-to-male sex reversal in response to various environmental changes such as temperature, hypoxia, and green light. Interestingly, we found that 5 days of starvation during sex differentiation caused female-to-male sex reversal. In this situation, the metabolism of pantothenate and fatty acid synthesis plays an important role in sex reversal. Metabolism is associated with other biological factors such as germ cells, HPG axis, lipids, and epigenetics, and supplys substances and acts as signal transducers. In this review, we discuss the importance of metabolism during sex differentiation and how metabolism contributes to sex differentiation.
Topics: Animals; Female; Germ Cells; Male; Oryzias; Sex Determination Analysis; Sex Determination Processes; Sex Differentiation
PubMed: 34284403
DOI: 10.1159/000515281 -
Biology of Sex Differences Jun 2022In this systematic review, we highlight the differences between the male and female zebrafish brains to understand their differentiation and their use in studying... (Review)
Review
In this systematic review, we highlight the differences between the male and female zebrafish brains to understand their differentiation and their use in studying sex-specific neurological diseases. Male and female brains display subtle differences at the cellular level which may be important in driving sex-specific signaling. Sex differences in the brain have been observed in humans as well as in non-human species. However, the molecular mechanisms of brain sex differentiation remain unclear. The classical model of brain sex differentiation suggests that the steroid hormones derived from the gonads are the primary determinants in establishing male and female neural networks. Recent studies indicate that the developing brain shows sex-specific differences in gene expression prior to gonadal hormone action. Hence, genetic differences may also be responsible for differentiating the brain into male and female types. Understanding the signaling mechanisms involved in brain sex differentiation could help further elucidate the sex-specific incidences of certain neurological diseases. The zebrafish model could be appropriate for enhancing our understanding of brain sex differentiation and the signaling involved in neurological diseases. Zebrafish brains show sex-specific differences at the hormonal level, and recent advances in RNA sequencing have highlighted critical sex-specific differences at the transcript level. The differences are also evident at the cellular and metabolite levels, which could be important in organizing sex-specific neuronal signaling. Furthermore, in addition to having one ortholog for 70% of the human gene, zebrafish also shares brain structural similarities with other higher eukaryotes, including mammals. Hence, deciphering brain sex differentiation in zebrafish will help further enhance the diagnostic and pharmacological intervention of neurological diseases.
Topics: Animals; Brain; Female; Gonads; Male; Mammals; Sex Characteristics; Sex Differentiation; Zebrafish
PubMed: 35715828
DOI: 10.1186/s13293-022-00442-2 -
The International Journal of... 2018Our understanding of avian sex determination and gonadal development is derived primarily from the studies in the chicken. Analysis of gynandromorphic chickens and... (Review)
Review
Our understanding of avian sex determination and gonadal development is derived primarily from the studies in the chicken. Analysis of gynandromorphic chickens and experimental chimeras indicate that sexual phenotype is at least partly cell autonomous in the chicken, with sexually dimorphic gene expression occurring in different tissue and different stages. Gonadal sex differentiation is just one of the many manifestations of sexual phenotype. As in other birds, the chicken has a ZZ male: ZW female sex chromosome system, in which the male is the homogametic sex. Most evidence favours a Z chromosome dosage mechanism underling chicken sex determination, with little evidence of a role for the W chromosome. Indeed, the W appears to harbour a small number of genes that are un-related to sexual development, but have been retained because they are dosage sensitive factors. As global Z dosage compensation is absent in birds, Z-linked genes may direct sexual development in different tissues (males having on average 1.5 to 2 times the expression level of females). In the embryonic gonads, the Z-linked DMRT1 gene plays a key role in testis development. Beyond the gonads, other combinations of Z-linked genes may govern sexual development, together with a role for sex steroid hormones. Gonadal DMRT1 is thought to activate other players in testis development, namely SOX9 and AMH, and the recently identified HEMGN gene. DMRT1 also represses ovarian pathway genes, such as FOXL2 and CYP19A1. A lower level of DMRT1 expression in the female gonads is compatible with activation of the ovarian pathway. Some outstanding questions include how the key testis and ovary genes, DMRT1 and FOXL2, are regulated. In addition, confirmation of the central role of these genes awaits genome editing approaches.
Topics: Animals; Aromatase; Cell Differentiation; Chick Embryo; Chickens; Dosage Compensation, Genetic; Female; Gene Dosage; Gene Expression Regulation, Developmental; Genome; Gonads; Male; Ovary; SOX9 Transcription Factor; Sex Chromosomes; Sex Determination Processes; Sex Differentiation; Testis
PubMed: 29616724
DOI: 10.1387/ijdb.170319cs