SRY (Sex-determining region Y) und Geschlechterunterschiede

Auf dem Y-Chromosom findet sich eine besondere Genregion, die sich wesentlich auf das Geschlecht auswirkt, die „Sex determinierende Region Y, oder kurz SRY.

Die Wikipedia dazu:

Die Sex determining region of Y-Gen (SRY), kurz als SRY-Gen bekannt, kodiert einen Transkriptionsfaktor – den Hoden-determinierenden Faktor (TDF für engl. Testis-determining factor) –, der zur (HMG)-Box-Proteinfamilie von DNA-Bindungsproteinen gehört. Das SRY-Gen wird neben anderen Genen zur Geschlechtsdetermination beim Menschen und anderen Säugetieren verwendet. Die meisten Säugetiere besitzen zu diesem Zweck ein weiteres Gen, UBE1. SRY liegt im Normalfall auf dem kurzen Arm des Y-Chromosom des Menschen. Entsprechend haben Menschen, die dieses Chromosom mit dem entsprechenden Gen besitzen, im Normalfall einen männlichen Phänotypus. Dabei ist es unerheblich, wie viele Kopien des X-Chromosoms vorliegen, auch Menschen mit einem multiplen X-Chromosom (Klinefelter-Syndrom) haben diesen. Das durch das Gen kodierte Protein Hoden-determinierender Faktor steuert die weitere Entwicklung zum männlichen Geschlecht. In seltenen Fällen kann das SRY-Gen auf dem Y-Chromosom fehlen oder durch Mutationen inaktiviert sein, wodurch Menschen mit diesem fehlerhaften Chromosom sich zu sterilen XY-Frauen entwickeln. Außerdem ist es möglich, dass das Gen durch Translokation auf das X-Chromosom gelangt, wodurch auch bei einem XX-Satz sterile männliche Individuen entstehen (XX-Mann).

Eine Kurzdarstellung des Vorganges findet sich auch in der englischen Wikipedia

During gestation, the cells of the primordial gonad that lie along the urogenital ridge are in a bipotential state, meaning they possess the ability to become either male cells (Sertoli and Leydig cells) or female cells (follicle cells and Theca cells). SRY initiates testis differentiation by activating male-specific transcription factors that allow these bipotential cells to differentiate and proliferate. SRY accomplishes this by upregulating SOX9, a transcription factor with a DNA-binding site very similar to SRY’s. SOX9 in turn upregulates fibroblast growth factor 9 (Fgf9), which is necessary for proper Sertoli cell differentiation. Fgf9 then feeds back and upregulates SOX9. SOX9 can also upregulate itself by binding to its own enhancer region (positive feedback loop). Once proper SOX9 levels are reached, the bipotential cells of the gonad begin to differentiate into Sertoli cells. Additionally, cells expressing SRY will continue to proliferate to form the primordial testis. While this constitutes the basic series of events, this brief review should be taken with caution since there are many more factors that influence sex differentiation.

Es scheint auch direkte Auswirkungen dieser Gene auf das Gehirn zu geben:

Sexual differentiation of the brain is thought to be regulated by hormonal signals from the developing male gonad. However, more-recent experimental and clinical data throw some doubt on the general validity of the „classical“ steroid hypothesis and suggest that additional intervening factors or mechanisms need to be considered. In particular, it is now envisaged that neurons are capable of acquiring sex-specific properties independently of their hormonal environment. Here we show that two Y-chromosomal genes involved in sex determination of the gonad, SRY and ZFY, are transcribed in hypothalamus, and frontal and temporal cortex of the adult male human brain. These genes are candidates for male-specific transcriptional regulators that could confer upon human brain cells the potential for hormone-independent realization and maintenance of genetic sex.

Quelle: The Y-chromosomal genes SRY and ZFY are transcribed in adult human brain.

Neben dem hormonellen System werden also anscheinend einige weitere Unterschiede direkt über die Gene bewirkt.

Eine weitere Studie dazu:

The central dogma of mammalian brain sexual differentiation has contended that sex steroids of gonadal origin organize the neural circuits of the developing brain [1]. Recent evidence has begun to challenge this idea and has suggested that, independent of the masculinizing effects of gonadal secretions, XY and XX brain cells have different patterns of gene expression that influence their differentiation and function [2]. We have previously shown that specific differences in gene expression exist between male and female developing brains and that these differences precede the influences of gonadal hormones [3]. Here we demonstrate that the Y chromosome-linked, male-determining gene Sry is specifically expressed in the substantia nigra of the adult male rodent in tyrosine hydroxylase-expressing neurons. Furthermore, using antisense oligodeoxynucleotides, we show that Sry downregulation in the substantia nigra causes a statistically significant decrease in tyrosine hydroxylase expression with no overall effect on neuronal numbers and that this decrease leads to motor deficits in male rats. Our studies suggest that Sry directly affects the biochemical properties of the dopaminergic neurons of the nigrostriatal system and the specific motor behaviors they control. These results demonstrate a direct male-specific effect on the brain by a gene encoded only in the male genome, without any mediation by gonadal hormones.

Quelle: Direct Regulation of Adult Brain Function by the Male-Specific Factor SRY

Und eine weitere Studie:

Biological differences between men and women contribute to many sex-specific illnesses and disorders. Historically, it was argued that such differences were largely, if not exclusively, due to gonadal hormone secretions. However, emerging research has shown that some differences are mediated by mechanisms other than the action of these hormone secretions and in particular by products of genes located on the X and Y chromosomes, which we refer to as direct genetic effects. This paper reviews the evidence for direct genetic effects in behavioral and brain sex differences. We highlight the `four core genotypes‘ model and sex differences in the midbrain dopaminergic system, specifically focusing on the role of Sry. We also discuss novel research being done on unique populations including people attracted to the same sex and people with a cross-gender identity. As science continues to advance our understanding of biological sex differences, a new field is emerging that is aimed at better addressing the needs of both sexes: gender-based biology and medicine. Ultimately, the study of the biological basis for sex differences will improve healthcare for both men and women.

Quelle: The Genetics of Sex Differences in Brain and Behavior

In dieser Studie wird auch zuerst der klassische Weg der Begründung von Geschlechterunterschieden durch Hormone dargestellt:

Sexual development in mammals can be divided into two main components: sex determination and sex differentiation [208]. `Sex determination‘ is the process by which the bipotential gonad develops into either a testis or an ovary, which depends exclusively on genetics. `Sex differentiation‘ is the development of other internal reproductive structures, the external genitalia, and non-gonadal sex differences. Unlike sex determination, sex differentiation is driven by gonadal hormones. It was widely believed that sex differences that emerged after sex determination were largely due to the actions of gonadal hormones. Examples of this pervasive view include writings from Lillie in 1939 (“[T]he mechanism of sex differentiation is taken over by extracellular agents, the male and female hormones.”

Soweit so klar. Auch hier werden aber direkte genetische Effekte benannt:

Recently, it was found that gonadal hormones might not be the sole contributor to male- and female-typical development. Genes encoded on the sex chromosomes that directly act on the brain to influence neural developmental and sex-specific behaviors have been identified—an example of what we describe as direct genetic effects [215; 216]. When we use this term, we refer to effects arising from the expression of X and Y genes within non-gonadal cells that result in sex differences in the functions of those cells or target cells. Such direct genetic actions are wide-ranging and can include effects of locally produced hormones or other non-hormonal messenger molecules. For example, sex differences arising in the brain from differential paracrine secretion of neurosteroids would be considered a direct genetic effect. The commonality among these actions is that they are not dependent on mediation by hormones secreted by the gonads. In many cases, the identity of the messenger molecules have yet to be identified. This review will now focus on examples in which sex differences in behaviors are unlikely to be influenced by only the action of gonadal hormonal secretions and may in fact be due to direct genetic effects.

Es sollen beispielsweise die folgenden drei Gebiete direkt durch die Gene beeinflusst sein:

5.1.2 Lateral septum

One clear example of the role of sex-chromosome genes in brain phenotypes can be found in the lateral septum. The lateral septum is part of the limbic system and is involved in stress-related behaviors. This nucleus is denser in male brains compared to female brains. However, it was found that the vasopressin fiber density was greater in the lateral septum of XY−Sry and XY− mice compared to XX and XXSry mice [215]. In addition, an examination of vasopressin fiber densities in animals with the same sex chromosome complement indicated a role for the action of gonadal steroid hormones. No interaction was observed between gonadal sex and sex chromosomes [216].

5.1.3 Addiction

On average, women use addictive drugs at lower levels than men, but women become addicted to drugs more rapidly than men [248]. Based on the FCG model, Quinn et al. showed that this difference could be attributed to the differences in the complement of the sex chromosomes and not to the gonadal secretions and/or the expression of the Sry gene. XX mice developed habitual behavior more rapidly than the XY animals independent of their gonadal phenotype and even after gonadectomy. This implies that neither gonadal sex nor circulating steroid hormones exert major effects on the development of habit-driven behavior in mice [182].

5.1.4 Aggression

Males typically exhibit more aggressive behaviors compared to females [249; 250; 251]. Recent reports have shown that aggression latencies are strongly influenced by the simultaneous action of gonadal hormones and sex chromosomes. Using the four core genotypes model, it was found that a significant interaction exists between the two variables. In this model, the XX females appeared to be slower at displaying aggressive behavior on their first encounter with an intruder compared to animals in all other groups [215].

Hier könnten also bestimmten Unterschiede direkt über Gene vorliegen. Möglicherweise sind hier solche Unterschiede wie etwa die Fight and Flight Reaktion von Männern gegenüber Tend and Befriend bei Frauen als Stressreaktionen in dem Bereich geregelt.

Es spricht damit einiges dafür, dass einige Unterschiede zwischen den Geschlechtern nicht nur über die Hormone geschehen, sondern „direkter“ über die Gene.