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Sex differences in molecular neuroscience: from fruit flies to humans

Nature Reviews Neuroscience volume 11, pages 9–17 (2010)Cite this article

Subjects

Key Points

  • There are sex biases in the expression of many genes in the brains of species ranging from Drosophila melanogaster to humans.

  • The mechanisms controlling sex differences during the development of the CNS in D. melanogaster and nematodes are well known. Conversely, little is known about the early regulation of sex differences in the brains of vertebrates, except for the well-established actions of sex hormones.

  • Independent of hormonal control, several recently published results point to the sex chromosome complement as a main player in establishing sex differences in the CNS.

  • Genes encoded on the X chromosome that escape X inactivation are among those recently proposed to control sex differences during brain development.

  • Other regulatory candidates include genes on the Y chromosome, some of which are expressed early during development.

  • Proposed molecular mechanisms for the control of sex-biased expression differences include differential splicing and epigenetic control.

Abstract

A plethora of discoveries relating to sex influences on brain function is rapidly moving this field into the spotlight for most areas of neuroscience. The domain of molecular or genetic neuroscience is no exception. The goal of this article is to highlight key developments concerning sex-based dimorphisms in molecular neuroscience, describe control mechanisms regulating these differences, address the implications of these dimorphisms for normal and abnormal brain function and discuss what these advances mean for future work in the field. The overriding conclusion is that, as for neuroscience in general, molecular neuroscience has to take into account potential sex influences that might modify signalling pathways.

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Figure 1: Early genetic control of sex determination in the CNS.
Figure 2: Regulation of gene expression by hormone receptors.

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Acknowledgements

The authors would like to thank the Swedish Börgströms Foundation (E.J.) and the National Institute of Mental Health (R01 to L.C.) for their support.

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Authors and Affiliations

  1. Department of Genetics and Development, Evolutionary Biology Centre, Uppsala University, SE-75236, Sweden

    Elena Jazin

  2. Center for the Neurobiology of Learning and Memory, University of California, Irvine, 92697-3800, California, USA

    Larry Cahill

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  1. Elena Jazin
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Correspondence to Elena Jazin.

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Glossary

Epigenetics

Changes in phenotype caused by mechanisms other than changes in the underlying DNA sequence (hence the name epi — 'in addition to' — genetics).

Sex bias

(Also known as sexual dimorphism.) The systematic difference in form or function between individuals of a different sex in the same species. Body features that are affected by sex bias include colour of skin or coat (fur, feathers, et cetera), size and the presence or absence of body parts or behaviours.

Gonadal sex determination

The biological mechanism that induces the development of the ovaries or testes in an organism. In many species it is genetically determined by the presence of specific chromosomes called sex chromosomes.

Gonadal hormones

(Also called sex steroids or sex hormones.) Hormones produced in the gonads, including oestrogen and testosterone. These hormones interact with oestrogen or androgen receptors.

Gonad

The organ that makes gametes, the germ cells used for fertilization. The gonads in males are the testes or testicles and the gonads in females are the ovaries.

Genome-wide expression analysis

Examination of RNA expression variation across the human genome, designed to identify associations with observable traits.

Alternative splicing

(Also known as differential splicing.) Variations of the splicing mechanism in which the exons of the primary gene transcript are separated and reconnected so as to produce alternative ribonucleotide arrangements.

SRY

(Sex-determining region Y). A gene encoded on the Y chromosome in many placental mammals. It encodes a transcription factor that initiates the formation of the testicles in males.

X inactivation

The process by which one of the two X chromosomes in female mammals is not expressed. Inactivation occurs at random in each cell, resulting in a mosaic of expression in each XX individual.

Paralogues

One type of homologous gene. Homologous genes are those that have a common ancestor. Paralogous genes were separated during evolution by a gene duplication event.

Genomic imprinting

Different expression of a gene, depending on the sex of the parent who transmits it. One of the alleles is imprinted or marked to be silenced, for example by methylation.

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Jazin, E., Cahill, L. Sex differences in molecular neuroscience: from fruit flies to humans. Nat Rev Neurosci 11, 9–17 (2010). https://doi.org/10.1038/nrn2754

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