Modular Genetic Control of Sexually Dimorphic Behaviors

Xu, Xin; Coats, Jennifer K.; Yang, Cindy F.; Wang, Amy; Ahmed, Osama M.; Alvarado, Maricruz; Izumi, Tetsuro; Shah, Nirao M.

doi:10.1016/j.cell.2012.02.026

Cited by 19 publications

(23 citation statements)

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“…For the genes that are expressed in a sex-specific manner, we confirmed their coexpression with Esr1, Esr2, and Pgr, which is in accordance with their regulation by gonadal steroids (19). Lack of coexpression with Ar may reflect the fact that many testosterone effects on the HY are mediated by estrogen receptors after aromatization of testosterone into estradiol.…”

Section: Discussionsupporting

confidence: 57%

“…Among the tested genes we identified two estrogen-regulated genes: Irs4, a previously known ESR1 target (19); and Magel2, a previously unidentified ESR1 target. Loss of Magel2 leads to impaired reproduction, providing an immediate link to estrogen regulation (34).…”

Section: Discussionmentioning

confidence: 99%

“…It is as yet unclear whether the significant coexpression with Pgr reflects simply coexpression of Esr1 and Pgr or also points to progesterone regulation of these genes. Regardless, we extended the coexpression between sexually dimorphic genes to extrahypothalamic sites, pointing to a parallel regulation in, at least, the PAL, a region that includes the bed nucleus of the stria terminalis, where regulation by (nonspecified) gonadal hormones has been observed (19).…”

Section: Discussionmentioning

confidence: 99%

“…Xu et al (19) showed that a set of 16 genes, including Esr1, has sexual dimorphic expression in the adult mouse HY. In addition, they showed that these 16 genes are sensitive to gonadal steroids (also in the male mouse brain) and that some are necessary for effects of estrogens on sexually dimorphic behavior (19), making this set of ESR1 targets in the HY quite valuable. Table S2 shows the correlation values for each of the 15 sexually dimorphic genes with Esr1 in whole brain, as well as in the HY, based on data from the ABA.…”

Section: Glucocorticoid-responsive Genes Are Highly Expressed With Grmentioning

confidence: 99%

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Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions

Mahfouz

Lelieveldt

Grefhorst

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Steroid receptors are pleiotropic transcription factors that coordinate adaptation to different physiological states. An important target organ is the brain, but even though their effects are well studied in specific regions, brain-wide steroid receptor targets and mediators remain largely unknown due to the complexity of the brain. Here, we tested the idea that novel aspects of steroid action can be identified through spatial correlation of steroid receptors with genome-wide mRNA expression across different regions in the mouse brain. First, we observed significant coexpression of six nuclear receptors (NRs) [androgen receptor (Ar), estrogen receptor alpha (Esr1), estrogen receptor beta (Esr2), glucocorticoid receptor (Gr), mineralocorticoid receptor (Mr), and progesterone receptor (Pgr)] with sets of steroid target genes that were identified in single brain regions. These coexpression relationships were also present in distinct other brain regions, suggestive of as yet unidentified coordinate regulation of brain regions by, for example, glucocorticoids and estrogens. Second, coexpression of a set of 62 known NR coregulators and the six steroid receptors in 12 nonoverlapping mouse brain regions revealed selective downstream pathways, such as Pak6 as a mediator for the effects of Ar and Gr on dopaminergic transmission. Third, Magel2 and Irs4 were identified and validated as strongly responsive targets to the estrogen diethylstilbestrol in the mouse hypothalamus. The brain-and genome-wide correlations of mRNA expression levels of six steroid receptors that we provide constitute a rich resource for further predictions and understanding of brain modulation by steroid hormones. neuroendocrinology | nuclear receptors | transcription regulation | estrogens | glucocorticoids S teroid receptors are part of the superfamily of nuclear receptors (NRs) that act as transcription factors regulating expression of numerous biologically important target genes (1). Their transcriptional activity is induced by steroid hormones, which respond to changed demands in terms of reproductive status, mineral balance, or stressful physical and psychological challenges. A crucial site of action is the brain, where these hormones have strong modulatory effects on physiological regulation, cognitive function, mood, and behavior. They do so by changing cellular responsiveness to a variety of neurotransmitters and peptides, and by inducing morphological changes (2, 3).Understanding the effects of steroid hormones on the brain faces the challenge to identify in as many as 900 different brain nuclei (4) both the highly cell-specific target genes that mediate the hormone effects (5, 6) and the signaling factors that mediate or influence steroid receptor signaling. The latter include proteins affecting prereceptor metabolism, interacting transcription factors (7), and downstream NR coregulator proteins (1). Even if the effects of steroid hormones are well-studied in specific regions (1, 8), overall, the brain steroid receptor targets and mediators ...

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Glucocorticoid-responsive Genes Are Highly Expressed With Grmentioning

confidence: 99%

See 2 more Smart Citations

Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions

Mahfouz

Lelieveldt

Grefhorst

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

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“…These steroid hormone receptors are cognate nuclear receptors, which upon ligand binding translocate to the nucleus to regulate expression of target genes. Target genes downstream of hormone receptors have been identified in the brain and are expressed in overlapping but non-identical patterns, raising the possibility that these genes regulate different aspects of male mating [15].…”

Section: Separable Genes Control Distinct Behavioral Parametersmentioning

confidence: 99%

Modular genetic control of innate behaviors

Xu¹

2013

BioEssays

Self Cite

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Many complex behaviors are genetically hardwired. Based on previous findings on genetic control of mating and other behaviors in invertebrate and mammalian systems, I suggest that genetic control of complex behaviors is modular: first, dedicated genes specify different behavioral patterns; secondly, separable genetic networks govern distinct behavioral components. I speculate that modular genetic encoding of complex behaviors may in part reflect modularity in brain development and function.

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Developmental expression of the neuroligins and neurexins in fragile X mice

Lai

Doering

Foster

2015

J of Comparative Neurology

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Neuroligins and neurexins are transsynaptic proteins involved in the maturation of glutamatergic and GABAergic synapses. Research has identified synaptic proteins and function as primary contributors to the development of fragile X syndrome. Fragile X mental retardation protein (FMRP), the protein that is lacking in fragile X syndrome, binds neuroligin-1 and -3 mRNA. Using in situ hybridization, we examined temporal and spatial expression patterns of neuroligin (NLGN) and neurexin (NRXN) mRNAs in the somatosensory (S1) cortex and hippocampus in wild-type (WT) and fragile X knockout (FMR1-KO) mice during the first 5 weeks of postnatal life. Genotype-based differences in expression included increased NLGN1 mRNA in CA1 and S1 cortex, decreased NLGN2 mRNA in CA1 and dentate gyrus (DG) regions of the hippocampus, and increased NRXN3 mRNA in CA1, DG, and S1 cortex between female WT and FMR1-KO mice. In male mice, decreased expression of NRXN3 mRNA was observed in CA1 and DG regions of FMR1-KO mice. Sex differences in hippocampal expression of NLGN2, NRXN1, NRXN2, and NRXN3 mRNAs and in S1 cortex expression of NRXN3 mRNAs were observed WT mice, whereas sex differences in NLGN3, NRXN1, NRXN2, and NRXN3 mRNA expression in the hippocampus and in NLGN1, NRXN2 and NRXN3 mRNA expression in S1 cortex were detected in FMR1-KO mice. These results provide a neuroanatomical map of NLGN and NRXN expression patterns over postnatal development in WT and FMR1-KO mice. The differences in developmental trajectory of these synaptic proteins could contribute to long-term differences in CNS wiring and synaptic function.

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Modular Genetic Control of Sexually Dimorphic Behaviors

Cited by 19 publications

References 0 publications

Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions

Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions

Modular genetic control of innate behaviors

Developmental expression of the neuroligins and neurexins in fragile X mice

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