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Cited by 221Sexual Differentiation and DisordersEstrogen and related hormone effectsGenetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

Gene regulation by gonadal hormone receptors underlies brain sex differences

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Gegenhuber, B., Wu, M. V., Bronstein, R., Tollkuhn, J.·2022·Nature
DOI 10.1038/s41586-022-04686-1PMC PMC9159952
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Abstract

Abstract Oestradiol establishes neural sex differences in many vertebrates 1–3 and modulates mood, behaviour and energy balance in adulthood 4–8 . In the canonical pathway, oestradiol exerts its effects through the transcription factor oestrogen receptor-α (ERα) 9 . Although ERα has been extensively characterized in breast cancer, the neuronal targets of ERα, and their involvement in brain sex differences, remain largely unknown. Here we generate a comprehensive map of genomic ERα-binding sites in a sexually dimorphic neural circuit that mediates social behaviours. We conclude that ERα orchestrates sexual differentiation of the mouse brain through two mechanisms: establishing two male-biased neuron types and activating a sustained male-biased gene expression program. Collectively, our findings reveal that sex differences in gene expression are defined by hormonal activation of neuronal steroid receptors. The molecular targets we identify may underlie the effects of oestradiol on brain development, behaviour and disease.

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  • The extended amygdala, including the BNST, is especially sensitive to steroid hormones.

    “The extended amygdala, which includes the bed nucleus of the stria terminalis (BNST), is especially sensitive to steroid hormones (28).”

    From Sexual differentiation of neural mechanisms of stress sensitivity during puberty (2023) · cites this paper as [28]

    The 'Genomic targets of ERα in the brain' section reports that oestradiol regulates genes in the BNSTp and identifies the posterior medial amygdala as another region where ERα regulates behaviour. This supports hormone responsiveness in the regions studied, but the paper does not characterize the extended amygdala as a whole or establish that it is especially sensitive relative to other regions. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Gonadal hormones shape brain structure, function, and gene expression networks that could influence stress responses.

    “Although the cause of these differences is unknown, other studies show that gonadal hormones shape brain structure (23–26), function (27), and gene expression networks (28) that could influence stress responses.”

    From Sexual differentiation of neural mechanisms of stress sensitivity during puberty (2023) · cites this paper as [28]

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Cited by

Sorted by citations

Authors
Gegenhuber, B., Wu, M. V., Bronstein, R., & Tollkuhn, J.
Affiliations
Cold Spring Harbor Laboratory (US)
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2022-05-04
Volume
606
Issue
7912
Pages
153-159
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-022-04686-1
PMC
PMC9159952
OpenAlex
W4229007424
Cited by
221
References
12
Citations by year
2026: 44 · 2025: 58 · 2024: 63 · 2023: 37 · 2022: 19
FWCI
14.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Cold Spring Harbor Laboratory
  • Simons Foundation Autism Research Initiative
  • Stanley Family Foundation
  • National Institutes of Health (1s10od028632-01, MH113628, 5P30CA045508, 5p30ca045508-35)
  • National Institute of Mental Health (F31MH124365, R01MH113628)
  • National Cancer Institute (P30-CA045508)
  • National Institute of General Medical Sciences (T32GM065094)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
Keywords
estrogen receptor alpha, estradiol, sexual differentiation of the brain, sex differences in gene expression, social behavior, mouse brain
MeSH terms
Animals, Brain, Estradiol, Female, Gene Expression Regulation, Male, Sex Characteristics, Estrogen Receptor alpha, Mice

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