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WIREs Dev Biol
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Signatures of sex: Sex differences in gene expression in the vertebrate brain

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Abstract Women and men differ in disease prevalence, symptoms, and progression rates for many psychiatric and neurological disorders. As more preclinical studies include both sexes in experimental design, an increasing number of sex differences in physiology and behavior have been reported. In the brain, sex‐typical behaviors are thought to result from sex‐specific patterns of neural activity in response to the same sensory stimulus or context. These differential firing patterns likely arise as a consequence of underlying anatomic or molecular sex differences. Accordingly, gene expression in the brains of females and males has been extensively investigated, with the goal of identifying biological pathways that specify or modulate sex differences in brain function. However, there is surprisingly little consensus on sex‐biased genes across studies and only a handful of robust candidates have been pursued in the follow‐up experiments. Furthermore, it is not known how or when sex‐biased gene expression originates, as few studies have been performed in the developing brain. Here we integrate molecular genetic and neural circuit perspectives to provide a conceptual framework of how sex differences in gene expression can arise in the brain. We detail mechanisms of gene regulation by steroid hormones, highlight landmark studies in rodents and humans, identify emerging themes, and offer recommendations for future research. This article is categorized under: Nervous System Development > Vertebrates: General Principles Gene Expression and Transcriptional Hierarchies > Regulatory Mechanisms Gene Expression and Transcriptional Hierarchies > Sex Determination
Mechanisms of ERα‐mediated gene regulation. Estrogen receptor α (ERα) acts through various binding partners and intracellular signaling pathways to regulate gene expression in a tissue‐ and cell‐type‐specific manner. (a) Following ligand binding, ERα can directly influence transcription by binding canonical EREs, AP‐1 transcription factor complex, or PFs, which infiltrate heterochromatin and impart cell‐type‐specificity to ERα genomic binding (Droog, Mensink, & Zwart, ; Gertz et al., ). ERα also receives PTMs from diverse signaling pathways independent of ligand (Bennesch & Picard, ). Many extracellular molecules, such as growth factors, cytokines, and peptide hormones, can initiate ligand‐independent activation of ERα. (b) ERα can also indirectly regulate gene expression by controlling the phosphorylation of cAMP response element (CRE) binding protein (CREB). CREB specifically recruits CREB‐binding protein (CBP)—A transcriptional coactivator that serves a dual function in gene regulation as a histone acetyltransferase and scaffold for transcriptional machinery (Dyson & Wright, )
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Sex differences in steroid hormone receptor expression in the mouse brain. Sex differences in steroid hormone receptor expression have been reported in several brain areas involved in social behaviors. These areas include the anteroventral periventricular nucleus (AVPV), medial amygdala (MeA) posterior dorsal (MePD), and posterior ventral (MePV) regions, medial preoptic area of the hypothalamus (MPOA), posterior bed nucleus of the stria terminalis (BNSTp), and ventrolateral region of the ventromedial hypothalamus (VMHvl). AR, androgen receptor; ERα, estrogen receptor α; ERβ, estrogen receptor β; PR, progesterone receptor
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Intersection of developmental testosterone surges with neurodevelopmental events. Male mice (a) and humans (b) experience developmental T surges that delineate critical periods for sexual differentiation of the brain. Human testes begin to secrete T at approximately week 8 of gestation, peaking around week 16 and then declining until week 24. Fetal T levels are nearly as high as those during puberty. There is also elevated T during months 1–3 of infancy. Mouse testes become active in fetal development, and mice undergo a T surge on the day of birth. The testes are then inactive until puberty, which begins around postnatal week 4. At this time, the brain is still undergoing significant neuronal migration, particularly of inhibitory interneurons, while gliogenesis and synaptogenesis are still increasing. Human brain development occurs on a much longer timescale with the bulk of neuronal proliferation occurring during the fetal T surge. Events that occur during T surges are likely to give rise to sex differences in brain function, as female ovaries do not undergo significant hormone release until puberty
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Sex‐biased or estrogen‐regulated genes identified in multiple studies. Shown in bold type are genes identified in at least two papers as showing sex‐biased or hormone‐regulated expression in the brain. Superscript letters indicate the publications. Many estrogen‐regulated genes have also been found in screens for activity‐dependent gene expression (gray gene names). Underlined genes have been confirmed by histology. Not shown are steroid hormone receptors and aromatase, which have a well‐established sex bias
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Histological validation of sex differences in gene expression. In situ hybridization for two genes identified in a screen for sex differences in gene expression. Sytl4 is expressed more highly in male BNST, and its expression is decreased in the absence of circulating gonadal hormones (a–d). Brs3 is more abundant in female BNST (e–h) and MeA (i‐l) and is upregulated in castrate males but unchanged in castrate females (Reprinted with permission from Xu et al., . Copyright 2012 Cell Press)
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Sex differences in activity‐dependent gene expression. Estradiol and other steroid hormones can induce sex differences in gene expression via activity‐dependent transcription. (a) During proestrus, high levels of estrogens can activate neurons (orange bordered cells) in brain areas such as the MPOA (McHenry et al., ) or VTA (Calipari et al., ). Neural activity increases calcium release, CREB phosphorylation and upregulation of IEGs such as Fos (West et al., ). IEGs activate or repress cell‐type‐specific LRGs. Shown here is the growth factor Bdnf. This mechanism could lead to distinct gene expression profiles between high‐estrogen proestrus females and low‐estrogen diestrus females or males as in Duclot and Kabbaj (). (b) Neural activity in select hormone‐responsive neurons could be propagated to downstream brain areas, which would then report their own unique signature of activity‐regulated genes. This process could induce sex differences in gene expression in areas that do not express steroid hormone receptors. (c) A stimulus may activate distinct populations of neurons in the same brain area in males and females (Ishii et al., ), causing sex differences in both local activity‐responsive genes and in the two downstream target brain areas
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Developmental programming of sex differences in gene expression. Two simplified scenarios by which perinatal estradiol signaling could drive persistent sex differences in gene expression. Depicted is a schematized postnatal BNST, which expresses more gene X in males than females at the bulk tissue level (bar graph). Circles, squares, and triangles correspond to different cell types in the BNST. In (a) transient exposure to estradiol results in permanent remodeling or reorganization at the promoter of gene X in a subset of BNST cells (circles) expressing ERα. This opened chromatin facilitates increased transcription of gene X, similar to estradiol upregulation of Ar expression in mouse BNST (Juntti et al., ). In (b) estradiol promotes cell survival in males relative to females. Estradiol increases expression of pro‐survival Bcl family genes that inhibit the BAX/BAK apoptosis pathway (Forger et al., ; Zup et al., ). In this model, although the expression of gene X in a distinct cell type is similar between males and females, the male BNST contains more X‐expressing cells. The gene X expression difference would appear similar in models a and b at the bulk tissue level. Thus cellular resolution is necessary to distinguish between models a and b
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