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Nat Neurosci. 2015 May;18(5):690-7. doi: 10.1038/nn.3988. Epub 2015 Mar 30.

Brain feminization requires active repression of masculinization via DNA methylation.

Author information

1
1] Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland, USA. [2] Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
2
Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
3
Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.
4
Neuroscience Department, Mt. Sinai School of Medicine, New York, New York, USA.

Abstract

The developing mammalian brain is destined for a female phenotype unless exposed to gonadal hormones during a perinatal sensitive period. It has been assumed that the undifferentiated brain is masculinized by direct induction of transcription by ligand-activated nuclear steroid receptors. We found that a primary effect of gonadal steroids in the highly sexually dimorphic preoptic area (POA) is to reduce activity of DNA methyltransferase (Dnmt) enzymes, thereby decreasing DNA methylation and releasing masculinizing genes from epigenetic repression. Pharmacological inhibition of Dnmts mimicked gonadal steroids, resulting in masculinized neuronal markers and male sexual behavior in female rats. Conditional knockout of the de novo Dnmt isoform, Dnmt3a, also masculinized sexual behavior in female mice. RNA sequencing revealed gene and isoform variants modulated by methylation that may underlie the divergent reproductive behaviors of males versus females. Our data show that brain feminization is maintained by the active suppression of masculinization via DNA methylation.

PMID:
25821913
PMCID:
PMC4519828
DOI:
10.1038/nn.3988
[Indexed for MEDLINE]
Free PMC Article

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