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Journal of Neuroscience Research Jan 2017A general theory of mammalian sexual differentiation is proposed. All biological sex differences are the result of the inequality in effects of the sex chromosomes,... (Review)
Review
A general theory of mammalian sexual differentiation is proposed. All biological sex differences are the result of the inequality in effects of the sex chromosomes, which are the only factors that differ in XX vs. XY zygotes. This inequality leads to male-specific effects of the Y chromosome, including expression of the testis-determining gene Sry that causes differentiation of testes. Thus, Sry sets up lifelong sex differences in effects of gonadal hormones. Y genes also act outside of the gonads to cause male-specific effects. Differences in the number of X chromosomes between XX and XY cells cause sex differences in expression (1) of Xist, (2) of X genes that escape inactivation, and (3) of parentally imprinted X genes. Sex differences in phenotype are ultimately the result of multiple, independent sex-biasing factors, hormonal and sex chromosomal. These factors act in parallel and in combination to induce sex differences. They also can offset each other to reduce sex differences. Other mechanisms, operating at the level of populations, cause groups of males to differ on average from groups of females. The theory frames questions for further study, and directs attention to inherent sex-biasing factors that operate in many tissues to cause sex differences, and to cause sex-biased protection from disease. © 2016 Wiley Periodicals, Inc.
Topics: Animals; Genotype; Humans; Phenotype; Sex Characteristics; Sex Chromosomes; Sex Differentiation
PubMed: 27870435
DOI: 10.1002/jnr.23884 -
Sexual Development : Genetics,... 2014Vertebrate reproduction depends on the function of 2 distinct gametes, sperm and eggs, which develop in 2 different organs, the testis and the ovary. Testes and ovaries... (Review)
Review
Vertebrate reproduction depends on the function of 2 distinct gametes, sperm and eggs, which develop in 2 different organs, the testis and the ovary. Testes and ovaries are composed of germ cells, supporting cells and interstitial cells. In this review, we describe the origin and the fate of these cell lineages and how they interact with each other to form sexually dimorphic reproductive organs in medaka. We delineate how the temporally different association and establishment of these lineages contribute to a variety of seemingly different sex differentiation processes among teleost fish. Thus, teleosts represent an intriguing group in which to study the fundamental processes of gonadal development through comparing conserved and unique mechanisms.
Topics: Animals; Female; Fishes; Gene Expression Regulation, Developmental; Gonads; Male; Ovary; Reproduction; Sex Differentiation; Testis
PubMed: 25034975
DOI: 10.1159/000364924 -
Asian Journal of Andrology 2017In many species, including mammals, sex determination is genetically based. The sex chromosomes that individuals carry determine sex identity. Although the genetic base... (Review)
Review
In many species, including mammals, sex determination is genetically based. The sex chromosomes that individuals carry determine sex identity. Although the genetic base of phenotypic sex is determined at the moment of fertilization, the development of testes or ovaries in the bipotential early gonads takes place during embryogenesis. During development, sex determination depends upon very few critical genes. When one of these key genes functions inappropriately, sex reversal may happen. Consequently, an individual's sex phenotype may not necessarily be consistent with the sex chromosomes that are present. For some time, it has been assumed that once the fetal choice is made between male and female in mammals, the gonadal sex identity of an individual remains stable. However, recent studies in mice have provided evidence that it is possible for the gonadal sex phenotype to be switched even in adulthood. These studies have shown that two key genes, doublesex and mad-3 related transcription factor 1 (Dmrt1) and forkhead box L2 (Foxl2), function in a Yin and Yang relationship to maintain the fates of testes or ovaries in adult mammals, and that mutations in either gene might have a dramatic effect on gonadal phenotype. Thus, adult gonad maintenance in addition to fetal sex determination may both be important for the fertility.
Topics: Animals; Female; Fertility; Forkhead Box Protein L2; Gene Expression Regulation, Developmental; Humans; Male; Sex Determination Processes; Sex Differentiation; Transcription Factors
PubMed: 28091399
DOI: 10.4103/1008-682X.194420 -
Sexual Development : Genetics,... 2022Transcriptional regulators related to the invertebrate sexual regulators doublesex and mab-3 occur throughout metazoans and control sex in most animal groups. Seven of... (Review)
Review
Transcriptional regulators related to the invertebrate sexual regulators doublesex and mab-3 occur throughout metazoans and control sex in most animal groups. Seven of these DMRT genes are found in mammals, and mouse genetics has shown that one, Dmrt1, plays a crucial role in testis differentiation, both in germ cells and somatic cells. Deletions and, more recently, point mutations affecting human DMRT1 have demonstrated that its heterozygosity is associated with 46,XY complete gonadal dysgenesis. Most of our detailed knowledge of DMRT1 function in the testis, the focus of this review, derives from mouse studies, which have revealed that DMRT1 is essential for male somatic and germ cell differentiation and maintenance of male somatic cell fate after differentiation. Moreover, ectopic DMRT1 can reprogram differentiated female granulosa cells into male Sertoli-like cells. The ability of DMRT1 to control sexual cell fate likely derives from at least 3 properties. First, DMRT1 functionally collaborates with another key male sex regulator, SOX9, and possibly other proteins to maintain and reprogram sexual cell fate. Second, and related, DMRT1 appears to function as a pioneer transcription factor, binding "closed" inaccessible chromatin and promoting its opening to allow binding by other regulators including SOX9. Third, DMRT1 binds DNA by a highly unusual form of interaction and can bind with different stoichiometries.
Topics: Animals; Female; Humans; Male; Mice; Germ Cells; Gonadal Dysgenesis; Sex Differentiation; Testis; Transcription Factors
PubMed: 34515237
DOI: 10.1159/000518272 -
Sexual Development : Genetics,... 2016Foxl2 is a member of the large family of Forkhead Box (Fox) domain transcription factors. It emerged during the last 15 years as a key player in ovarian differentiation... (Review)
Review
Foxl2 is a member of the large family of Forkhead Box (Fox) domain transcription factors. It emerged during the last 15 years as a key player in ovarian differentiation and oogenesis in vertebrates and especially mammals. This review focuses on Foxl2 genes in light of recent findings on their evolution, expression, and implication in sex differentiation in animals in general. Homologs of Foxl2 and its paralog Foxl3 are found in all metazoans, but their gene evolution is complex, with multiple gains and losses following successive whole genome duplication events in vertebrates. This review aims to decipher the evolutionary forces that drove Foxl2/3 gene specialization through sub- and neo-functionalization during evolution. Expression data in metazoans suggests that Foxl2/3 progressively acquired a role in both somatic and germ cell gonad differentiation and that a certain degree of sub-functionalization occurred after its duplication in vertebrates. This generated a scenario where Foxl2 is predominantly expressed in ovarian somatic cells and Foxl3 in male germ cells. To support this hypothesis, we provide original results showing that in the pea aphid (insects) foxl2/3 is predominantly expressed in sexual females and showing that in bovine ovaries FOXL2 is specifically expressed in granulosa cells. Overall, current results suggest that Foxl2 and Foxl3 are evolutionarily conserved players involved in somatic and germinal differentiation of gonadal sex.
Topics: Animals; Evolution, Molecular; Female; Forkhead Box Protein L2; Forkhead Transcription Factors; Germ Cells; Gonads; Humans; Male; Phylogeny; Sex Differentiation; Vertebrates
PubMed: 27441599
DOI: 10.1159/000447611 -
Philosophical Transactions of the Royal... Aug 2021So far, very few sex-determining genes have been identified in vertebrates and most of them, the so-called 'usual suspects', evolved from genes which fulfil essential... (Review)
Review
So far, very few sex-determining genes have been identified in vertebrates and most of them, the so-called 'usual suspects', evolved from genes which fulfil essential functions during sexual development and are thus already tightly linked to the process that they now govern. The single exception to this 'usual suspects' rule in vertebrates so far is the conserved salmonid sex-determining gene, (sexually dimorphic on the Y chromosome), that evolved from a gene known to be involved in regulation of the immune response. It is contained in a jumping sex locus that has been transposed or translocated into different ancestral autosomes during the evolution of salmonids. This special feature of , i.e. being inserted in a 'jumping sex locus', could explain how salmonid sex chromosomes remain young and undifferentiated to escape degeneration. Recent knowledge on the mechanism of action of demonstrates that it triggers its sex-determining action by deregulating oestrogen synthesis that is a conserved and crucial pathway for ovarian differentiation in vertebrates. This result suggests that has evolved to cope with a pre-existing sex differentiation regulatory network. Therefore, 'limited options' for the emergence of new master sex-determining genes could be more constrained by their need to tightly interact with a conserved sex differentiation regulatory network rather than by being themselves 'usual suspects', already inside this sex regulatory network. This article is part of the theme issue 'Challenging the paradigm in sex chromosome evolution: empirical and theoretical insights with a focus on vertebrates (Part I)'.
Topics: Animals; Salmonidae; Sex Determination Processes; Sex Differentiation
PubMed: 34247499
DOI: 10.1098/rstb.2020.0092 -
Endocrinology Nov 2021Significant sex differences exist across cellular, tissue organization, and body system scales to serve the distinct sex-specific functions required for reproduction.... (Review)
Review
Significant sex differences exist across cellular, tissue organization, and body system scales to serve the distinct sex-specific functions required for reproduction. They are present in all animals that reproduce sexually and have widespread impacts on normal development, aging, and disease. Observed from the moment of fertilization, sex differences are patterned by sexual differentiation, a lifelong process that involves mechanisms related to sex chromosome complement and the epigenetic and acute activational effects of sex hormones. In this mini-review, we examine evidence for sex differences in cellular responses to DNA damage, their underlying mechanisms, and how they might relate to sex differences in cancer incidence and response to DNA-damaging treatments.
Topics: Adaptation, Physiological; Aging; Animals; DNA Damage; DNA Repair; Female; Gonadal Steroid Hormones; Humans; Male; Sex Characteristics; Sex Differentiation
PubMed: 34478502
DOI: 10.1210/endocr/bqab192 -
International Journal of Molecular... Oct 2022For many decades to date, neuroendocrinologists have delved into the key contribution of gonadal hormones to the generation of sex differences in the developing brain... (Review)
Review
For many decades to date, neuroendocrinologists have delved into the key contribution of gonadal hormones to the generation of sex differences in the developing brain and the expression of sex-specific physiological and behavioral phenotypes in adulthood. However, it was not until recent years that the role of sex chromosomes in the matter started to be seriously explored and unveiled beyond gonadal determination. Now we know that the divergent evolutionary process suffered by X and Y chromosomes has determined that they now encode mostly dissimilar genetic information and are subject to different epigenetic regulations, characteristics that together contribute to generate sex differences between XX and XY cells/individuals from the zygote throughout life. Here we will review and discuss relevant data showing how particular X- and Y-linked genes and epigenetic mechanisms controlling their expression and inheritance are involved, along with or independently of gonadal hormones, in the generation of sex differences in the brain.
Topics: Female; Male; Animals; Sex Differentiation; Y Chromosome; Sex Chromosomes; Sex Characteristics; Gonadal Hormones; Brain; Epigenesis, Genetic; X Chromosome
PubMed: 36293143
DOI: 10.3390/ijms232012288 -
Cells Dec 2021The MAP3K1 is responsible for transmitting signals to activate specific MAP2K-MAPK cascades. Following the initial biochemical characterization, genetic mouse models... (Review)
Review
The MAP3K1 is responsible for transmitting signals to activate specific MAP2K-MAPK cascades. Following the initial biochemical characterization, genetic mouse models have taken center stage to elucidate how MAP3K1 regulates biological functions. To that end, mice were generated with the ablation of the entire gene, the kinase domain coding sequences, or ubiquitin ligase domain mutations. Analyses of the mutants identify diverse roles that MAP3K1 plays in embryonic survival, maturation of T/B cells, and development of sensory organs, including eye and ear. Specifically in eye development, loss-of-function was found to be autosomal recessive for congenital eye abnormalities, but became autosomal dominant in combination with and mutations. Additionally, mutation increased eye defects with an exposure to environmental agents such as dioxin. Data from eye developmental models reveal the nexus role of MAP3K1 in integrating genetic and environmental signals to control developmental activities. Here, we focus the discussions on recent advances in understanding the signaling mechanisms of MAP3K1 in eye development in mice and in sex differentiation from human genomics findings. The research works featured here lead to a deeper understanding of the in vivo signaling network, the mechanisms of gene-environment interactions, and the relevance of this multifaceted protein kinase in disease etiology and pathogenesis.
Topics: Animals; Embryonic Development; Gene Expression Regulation, Developmental; Gene-Environment Interaction; Humans; MAP Kinase Kinase Kinase 1; Mice; Sex Differentiation
PubMed: 35011600
DOI: 10.3390/cells11010034 -
Veterinary Medicine and Science Nov 2021Sexual differentiation can occur after exposure to aromatase into the left gonad at 6.5 days of incubation. Aromatase inhibitors work by inhibiting the action of the...
BACKGROUND
Sexual differentiation can occur after exposure to aromatase into the left gonad at 6.5 days of incubation. Aromatase inhibitors work by inhibiting the action of the aromatase, which converts androgens into estrogens by a process called aromatization.
OBJECTIVES
The aim of this study was to investigate the effect of in ovo exposure to the aromatase inhibitor from tomato and garlic extract on sexual differentiation and embryonic development in chicken embryos.
METHODS
Three hundred eggs divided into five groups: Control 1 (CO; no injection); control 2 distilled water, DW; 0.1 ml/egg); garlic extract (GAR; 0.1 mg/egg); tomato extract (TOM; 0.1 mg/egg); and garlic and tomato extract mixed (ATM, 0.1 ml/egg). The solution was prepared and injected into the albumin from the thin end of the eggs on day five by using a 1 ml syringe with a 23-gauge needle. The embryonic test (embryo/egg weight) conducted at 7, 14 and 17 days of incubation. After hatching, feather sexing conducted to determine the initial male. Chicks sex was later confirmed on day 42 by an optical microscope lens.
RESULTS
The results revealed that there was a significant increase (p < 0.01) in embryonic growth traits in all experimental treatments as compared to control treatments. There was a significant increase (p < 0.01) in the percentage of hatchability for all experimental treatments compared to control treatments and a significant increase (p < 0.01) in chick quality including one-day-old chick length and body weight. All experimental treatments showed a significant increase (p < 0.01) in the male-to-female ratio compared to control treatments.
CONCLUSIONS
The effect of in ovo exposure to aromatase inhibitors stimulated female-to-male sex reversal and improved embryonic development.
Topics: Animals; Aromatase Inhibitors; Chick Embryo; Chickens; Embryonic Development; Feathers; Female; Male; Sex Differentiation
PubMed: 34472216
DOI: 10.1002/vms3.623