scholarly journals Female-specific target sites for both oestrogen and androgen in the teleost brain

2012 ◽  
Vol 279 (1749) ◽  
pp. 5014-5023 ◽  
Author(s):  
Towako Hiraki ◽  
Akio Takeuchi ◽  
Takayasu Tsumaki ◽  
Buntaro Zempo ◽  
Shinji Kanda ◽  
...  
Keyword(s):  
Sex Differences ◽  
Sexual Differentiation ◽  
Adult Brain ◽  
Specific Expression ◽  
Specific Target ◽  
Target Sites ◽  
Teleost Brain ◽  
Steroid Sensitivity ◽  
Female Specific ◽  
The Brain

To dissect the molecular and cellular basis of sexual differentiation of the teleost brain, which maintains marked sexual plasticity throughout life, we examined sex differences in neural expression of all subtypes of nuclear oestrogen and androgen receptors (ER and AR) in medaka. All receptors were differentially expressed between the sexes in specific nuclei in the forebrain. The most pronounced sex differences were found in several nuclei in the ventral telencephalic and preoptic areas, where ER and AR expression were prominent in females but almost completely absent in males, indicating that these nuclei represent female-specific target sites for both oestrogen and androgen in the brain. Subsequent analyses revealed that the female-specific expression of ER and AR is not under the direct control of sex-linked genes but is instead regulated positively by oestrogen and negatively by androgen in a transient and reversible manner. Taken together, the present study demonstrates that sex-specific target sites for both oestrogen and androgen occur in the brain as a result of the activational effects of gonadal steroids. The consequent sex-specific but reversible steroid sensitivity of the adult brain probably contributes substantially to the process of sexual differentiation and the persistent sexual plasticity of the teleost brain.

scholarly journals Epigenetic mechanisms in sexual differentiation of the brain and behaviour

2016 ◽  
Vol 371 (1688) ◽  
pp. 20150114 ◽  
Author(s):  
Nancy G. Forger
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Sexual Differentiation ◽  
Wide Distribution ◽  
Epigenetic Modifications ◽  
Epigenetic Mechanism ◽  
Epigenetic Mechanisms ◽  
Genome Wide ◽  
The Brain

Circumstantial evidence alone argues that the establishment and maintenance of sex differences in the brain depend on epigenetic modifications of chromatin structure. More direct evidence has recently been obtained from two types of studies: those manipulating a particular epigenetic mechanism, and those examining the genome-wide distribution of specific epigenetic marks. The manipulation of histone acetylation or DNA methylation disrupts the development of several neural sex differences in rodents. Taken together, however, the evidence suggests there is unlikely to be a simple formula for masculine or feminine development of the brain and behaviour; instead, underlying epigenetic mechanisms may vary by brain region or even by dependent variable within a region. Whole-genome studies related to sex differences in the brain have only very recently been reported, but suggest that males and females may use different combinations of epigenetic modifications to control gene expression, even in cases where gene expression does not differ between the sexes. Finally, recent findings are discussed that are likely to direct future studies on the role of epigenetic mechanisms in sexual differentiation of the brain and behaviour.

scholarly journals Sex Differences in the Epigenome: A Cause or Consequence of Sexual Differentiation of the Brain?

Genes ◽  
2019 ◽  
Vol 10 (6) ◽  
pp. 432 ◽  
Author(s):  
Bruno Gegenhuber ◽  
Jessica Tollkuhn
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Sexual Differentiation ◽  
Hormone Receptors ◽  
Neurological Diseases ◽  
Activity Patterns ◽  
Regulatory Elements ◽  
The Body ◽  
Epigenetic Mechanism ◽  
The Brain

Females and males display differences in neural activity patterns, behavioral responses, and incidence of psychiatric and neurological diseases. Sex differences in the brain appear throughout the animal kingdom and are largely a consequence of the physiological requirements necessary for the distinct roles of the two sexes in reproduction. As with the rest of the body, gonadal steroid hormones act to specify and regulate many of these differences. It is thought that transient hormonal signaling during brain development gives rise to persistent sex differences in gene expression via an epigenetic mechanism, leading to divergent neurodevelopmental trajectories that may underlie sex differences in disease susceptibility. However, few genes with a persistent sex difference in expression have been identified, and only a handful of studies have employed genome-wide approaches to assess sex differences in epigenomic modifications. To date, there are no confirmed examples of gene regulatory elements that direct sex differences in gene expression in the brain. Here, we review foundational studies in this field, describe transcriptional mechanisms that could act downstream of hormone receptors in the brain, and suggest future approaches for identification and validation of sex-typical gene programs. We propose that sexual differentiation of the brain involves self-perpetuating transcriptional states that canalize sex-specific development.

scholarly journals The Mouse Murr1 Gene Is Imprinted in the Adult Brain, Presumably Due to Transcriptional Interference by the Antisense-Oriented U2af1-rs1 Gene

2004 ◽  
Vol 24 (1) ◽  
pp. 270-279 ◽  
Author(s):  
Youdong Wang ◽  
Keiichiro Joh ◽  
Sadahiko Masuko ◽  
Hitomi Yatsuki ◽  
Hidenobu Soejima ◽  
...  
Keyword(s):  
Developmental Change ◽  
Adult Brain ◽  
Paternal Allele ◽  
Transcriptional Interference ◽  
Specific Expression ◽  
Biallelic Expression ◽  
Allele Specific ◽  
The Brain ◽  
Predominant Expression

ABSTRACT The mouse Murr1 gene contains an imprinted gene, U2af1-rs1, in its first intron. U2af1-rs1 shows paternal allele-specific expression and is transcribed in the direction opposite to that of the Murr1 gene. In contrast to a previous report of biallelic expression of Murr1 in neonatal mice, we have found that the maternal allele is expressed predominantly in the adult brain and also preferentially in other adult tissues. This maternal-predominant expression is not observed in embryonic and neonatal brains. In situ hybridization experiments that used the adult brain indicated that Murr1 gene was maternally expressed in neuronal cells in all regions of the brain. We analyzed the developmental change in the expression levels of both Murr1 and U2af1-rs1 in the brain and liver, and we propose that the maternal-predominant expression of Murr1 results from transcriptional interference of the gene by U2af1-rs1 through the Murr1 promoter region.

scholarly journals hebp3, a Novel Member of the Heme-Binding Protein Gene Family, Is Expressed in the Medaka Meninges With Higher Abundance in Females Due to a Direct Stimulating Action of Ovarian Estrogens

Endocrinology ◽  
2013 ◽  
Vol 154 (2) ◽  
pp. 920-930 ◽  
Author(s):  
Kiyoshi Nakasone ◽  
Yoshitaka Nagahama ◽  
Kataaki Okubo
Keyword(s):  
Sex Differences ◽  
Gene Family ◽  
Protein Gene ◽  
Sex Chromosome ◽  
Binding Protein ◽  
Heme Binding ◽  
Teleost Brain ◽  
Binding Protein Gene ◽  
Heme Binding Protein ◽  
The Brain

The brains of teleost fish exhibit remarkable sexual plasticity throughout their life span. To dissect the molecular basis for the development and reversal of sex differences in the teleost brain, we screened for genes differentially expressed between sexes in the brain of medaka (Oryzias latipes). One of the genes identified in the screen as being preferentially expressed in females was found to be a new member of the heme-binding protein gene family that includes hebp1 and hebp2 and was designated here as hebp3. The medaka hebp3 is expressed in the meninges with higher abundance in females, whereas there is no expression within the brain parenchyma. This female-biased expression of hebp3 is not attributable to the direct action of sex chromosome genes but results from the transient and reversible action of estrogens derived from the ovary. Moreover, estrogens directly activate the transcription of hebp3 via a palindromic estrogen-responsive element in the hebp3 promoter. Taken together, our findings demonstrate that hebp3 is a novel transcriptional target of estrogens, with female-biased expression in the meninges. The definite but reversible sexual dimorphism of the meningeal hebp3 expression may contribute to the development and reversal of sex differences in the teleost brain.

The 13th J. A. F. Stevenson Memorial Lecture Sexual differentiation of the brain: possible mechanisms and implications

1985 ◽  
Vol 63 (6) ◽  
pp. 577-594 ◽  
Author(s):  
Roger A. Gorski
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Sex Differences ◽  
Sexual Differentiation ◽  
Gonadal Hormones ◽  
Model Systems ◽  
Memorial Lecture ◽  
Actual Structure ◽  
The Central Nervous System ◽  
The Brain

The mammalian brain appears to be inherently feminine and the action of testicular hormones during development is necessary for the differentiation of the masculine brain both in terms of functional potential and actual structure. Experimental evidence for this statement is reviewed in this discussion. Recent discoveries of marked structural sex differences in the central nervous system, such as the sexually dimorphic nucleus of the preoptic area in the rat, offer model systems to investigate potential mechanisms by which gonadal hormones permanently modify neuronal differentiation. Although effects of these steroids on neurogenesis and neuronal migration and specification have not been conclusively eliminated, it is currently believed, but not proven, that the principle mechanism of steroid action is to maintain neuronal survival during a period of neuronal death. The structural models of the sexual differentiation of the central nervous system also provide the opportunity to identify sex differences in neurochemical distribution. Two examples in the rat brain are presented: the distribution of serotonin-immunoreactive fibers in the medial preoptic nucleus and of tyrosine hydroxylase-immunoreactive fibers and cells in the anteroventral periventricular nucleus. It is likely that sexual dimorphisms will be found to be characteristic of many neural and neurochemical systems. The final section of this review raises the possibility that the brain of the adult may, in response to steroid action, be morphologically plastic, and considers briefly the likelihood that the brain of the human species is also influenced during development by the hormonal environment.

scholarly journals Channel nuclear pore protein 54 directs sexual differentiation and neuronal wiring of female reproductive behaviors in Drosophila

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Mohanakarthik P. Nallasivan ◽  
Irmgard U. Haussmann ◽  
Alberto Civetta ◽  
Matthias Soller
Keyword(s):  
Sexual Differentiation ◽  
Egg Laying ◽  
Adult Brain ◽  
Nuclear Pore ◽  
Reproductive Behaviors ◽  
Mating Response ◽  
Nuclear Pore Protein ◽  
Sex Peptide ◽  
The Brain ◽  
Pore Protein

Abstract Background Female reproductive behaviors and physiology change profoundly after mating. The control of pregnancy-associated changes in physiology and behaviors are largely hard-wired into the brain to guarantee reproductive success, yet the gene expression programs that direct neuronal differentiation and circuit wiring at the end of the sex determination pathway in response to mating are largely unknown. In Drosophila, the post-mating response induced by male-derived sex-peptide in females is a well-established model to elucidate how complex innate behaviors are hard-wired into the brain. Here, we use a genetic approach to further characterize the molecular and cellular architecture of the sex-peptide response in Drosophila females. Results Screening for mutations that affect the sensitivity to sex-peptide, we identified the channel nuclear pore protein Nup54 gene as an essential component for mediating the sex-peptide response, with viable mutant alleles leading to the inability of laying eggs and reducing receptivity upon sex-peptide exposure. Nup54 directs correct wiring of eight adult brain neurons that express pickpocket and are required for egg-laying, while additional channel Nups also mediate sexual differentiation. Consistent with links of Nups to speciation, the Nup54 promoter is a hot spot for rapid evolution and promoter variants alter nucleo-cytoplasmic shuttling. Conclusions These results implicate nuclear pore functionality to neuronal wiring underlying the sex-peptide response and sexual differentiation as a response to sexual conflict arising from male-derived sex-peptide to direct the female post-mating response.

Inflammatory Signals and Sexual Differentiation of the Brain

2019 ◽  
Author(s):  
Margaret M. McCarthy
Keyword(s):  
Sex Differences ◽  
Sexual Differentiation ◽  
Developmental Disorders ◽  
Additional Risk Factor ◽  
Gonadal Steroid ◽  
Maternal Immune System ◽  
Prenatal Inflammation ◽  
And Behavior ◽  
Hormonal Milieu ◽  
The Brain

Sex differences in the brain are established by the differential gonadal steroid hormonal milieu experienced by developing male and female fetuses and newborns. Androgen production by the testis starts in males prior to birth resulting in a brief developmental window during which the brain is exposed to high levels of steroid. Androgens and aromatized estrogens program the developing brain toward masculinized physiology and behavior that is then manifest in adulthood. In rodents, the perinatal programming of sex-specific adult mating behavior provides a model system for exploring the mechanistic origins of brain sex differences. Microglia are resident in the brain and provide innate immunity. Previously considered restricted to response to injury, these cells are now thought to be major contributors to the sculpting of developing neural circuits. This role extends to being an important component of the sexual differentiation process and has opened the door for exploration into myriad other aspects of neuroimmunity and inflammation as possible determinants of sex differences. In humans, males are at greater risk for more frequent and/or more severe neuropsychiatric and neurological disorders of development, many of which include prenatal inflammation as an additional risk factor. Emerging clinical and preclinical evidence suggests male brains experience a higher inflammatory tone early in development, and this may have its origins in the maternal immune system. Collectively, these disparate observations coalesce into a coherent picture in which brain development diverges in males versus females due to a combination of gonadal steroid action and neuroinflammation, and the latter increases the risk to males of developmental disorders.

scholarly journals Dehydroepiandrosterone Metabolism by 3β-Hydroxysteroid Dehydrogenase/Δ5-Δ4 Isomerase in Adult Zebra Finch Brain: Sex Difference and Rapid Effect of Stress

Endocrinology ◽  
2004 ◽  
Vol 145 (4) ◽  
pp. 1668-1677 ◽  
Author(s):  
Kiran K. Soma ◽  
Noel A. Alday ◽  
Michaela Hau ◽  
Barney A. Schlinger
Keyword(s):  
Sex Differences ◽  
Sex Difference ◽  
Zebra Finch ◽  
Sex Steroids ◽  
Hydroxysteroid Dehydrogenase ◽  
Adult Brain ◽  
Brain And Behavior ◽  
Rapid Modulation ◽  
And Behavior ◽  
The Brain

Abstract Dehydroepiandrosterone (DHEA) is a precursor to sex steroids such as androstenedione (AE), testosterone (T), and estrogens. DHEA has potent effects on brain and behavior, although the mechanisms remain unclear. One possible mechanism of action is that DHEA is converted within the brain to sex steroids. 3β-Hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase (3β-HSD) catalyzes the conversion of DHEA to AE. AE can then be converted to T and estrogen within the brain. We test the hypothesis that 3β-HSD is expressed in the adult brain in a region- and sex-specific manner using the zebra finch (Taeniopygia guttata), a songbird with robust sex differences in song behavior and telencephalic song nuclei. In zebra finch brain, DHEA is converted by 3β-HSD to AE and subsequently to estrogens and 5α- and 5β-reduced androgens. 3β-HSD activity is highest in the diencephalon and telencephalon. In animals killed within 2–3 min of disturbance, baseline 3β-HSD activity in portions of the telencephalon is higher in females than males. Acute restraint stress (10 min) decreases 3β-HSD activity in females but not in males, and in stressed animals, telencephalic 3β-HSD activity is greater in males than in females. Thus, the baseline sex difference is rapidly reversed by stress. To our knowledge, this is the first demonstration of 1) brain region differences in DHEA metabolism by 3β-HSD, 2) rapid modulation of 3β-HSD activity, and 3) sex differences in brain 3β-HSD and regulation by stress. Songbirds are good animal models for studying the regulation and functions of DHEA and neurosteroids in the nervous system.

scholarly journals Neuroendocrine-Immune Crosstalk Shapes Sex-Specific Brain Development

Endocrinology ◽  
2020 ◽  
Vol 161 (6) ◽  
Author(s):  
Sheryl E Arambula ◽  
Margaret M McCarthy
Keyword(s):  
Sex Differences ◽  
Brain Development ◽  
Sexual Differentiation ◽  
Gonadal Hormones ◽  
Neuroimmune System ◽  
Overwhelming Evidence ◽  
Brain Structure And Function ◽  
New Research ◽  
And Function ◽  
The Brain

Abstract Sex is an essential biological variable that significantly impacts multiple aspects of neural functioning in both the healthy and diseased brain. Sex differences in brain structure and function are organized early in development during the critical period of sexual differentiation. While decades of research establish gonadal hormones as the primary modulators of this process, new research has revealed a critical, and perhaps underappreciated, role of the neuroimmune system in sex-specific brain development. The immune and endocrine systems are tightly intertwined and share processes and effector molecules that influence the nervous system. Thus, a natural question is whether endocrine-immune crosstalk contributes to sexual differentiation of the brain. In this mini-review, we first provide a conceptual framework by classifying the major categories of neural sex differences and review the concept of sexual differentiation of the brain, a process occurring early in development and largely controlled by steroid hormones. Next, we describe developmental sex differences in the neuroimmune system, which may represent targets or mediators of the sexual differentiation process. We then discuss the overwhelming evidence in support of crosstalk between the neuroendocrine and immune systems and highlight recent examples that shape sex differences in the brain. Finally, we review how early life events can perturb sex-specific neurodevelopment via aberrant immune activation.

scholarly journals An Analysis of the Implication of Estrogens and Steroid Receptor Coactivators in the Genetic Basis of Gender Incongruence

2021 ◽  
Author(s):  
Rosa Fernández ◽  
Karla Ramírez ◽  
Enrique Delgado-Zayas ◽  
Esther Gómez-Gil ◽  
Isabel Esteva ◽  
...  
Keyword(s):  
Sex Differences ◽  
Transcription Factors ◽  
Target Genes ◽  
Intimate Relationship ◽  
Brain Regions ◽  
Adult Brain ◽  
Neuronal Function ◽  
Cascade Effect ◽  
Steroid Receptor Coactivators ◽  
The Brain

In mammals, sex differences in the adult brain are established very early in development, when the brain is still very immature. In the case of having inherited the SRY gene, during embryogenesis, testosterone secreted by the testes enters the brain and is converted to estradiol by the aromatase. Then the estradiol acts by binding to intracellular estrogen receptors (ERs) located predominantly in neurons, masculinizing specific brain regions. But ERs are also transcription factors that, when they are exposed to their ligand, dimerize and form complexes with coactivator proteins and corepressors, modifying the transcription of multiple target genes in a cascade effect and ultimately neuronal function. Given the intimate relationship between steroids and brain dimorphism, and steroid coactivators and gene transcription, in the present work, we further explore the implication of ERs α and β, and steroid coactivators NCoA-1, NCoA-2, NCoA-3, NCoA-4, NCoA-5 and p300-CREBBP, in the genesis of brain dimorphism. Based on our data, we believe that the coactivators NCOA-1, NCOA-2 and p300-CREBBP could be considered as candidate genes for GI.

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