Brain Function Regulation by SRY

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Recent research has challenged the theory that gonadal sex steroids are exclusively responsible for organizing neural circuits in mammalian brains during development by suggesting a direct role of the sex chromosomes. These investigators had previously demonstrated that specific differences in gene expression exist between male and female developing brains and that these differences precede the influences of gonadal hormones.¹ In the present study, Dewing and colleagues investigated the role of the Y-chromosome-linked, male-determining gene Sry in adult male rodents – specifically on tyrosine hydroxylase (TH)-expressing neurons in the substantia nigra (SN) and striatum. Brain mapping studies demonstrated that SRY protein is observed in all regions of the SN, with most SRY immunoreactive cells in the pars compacta region of adult male mouse and rat brains. Furthermore, SRY protein is produced in the adult male mouse SN and is localized exclusively in TH-positive neurons. The SRY staining was absent in the female mouse SN.

Effects of Sry antisense oligodeoxynucleotides (ODN) in the SN were assessed by akinesia and limb-use asymmetry tests. Data showed downregulation in the SN associated with reduced motor behaviors; ie, decreased limb use and steps taken in limbs contralateral to unilateral antisense ODN infusions that were also associated with decreases in TH expression in the SN.

The authors concluded that Sry is expressed in specific mammalian adult male brain regions and its role in the SN is to maintain biochemical and motor functions of dopaminergic neurons. Further, they indicated Sry may directly and indirectly control TH expression in the SN.

Dewing P, Chiang CWK, Sinchak K, Sim H, Fernagut P-O, Kelly S et al. Direct regulation of adult brain function by the male-specific factor SRY. Curr Biol. 2006;16:415–420.

Editor’s Comment

This report adds to the increasing body of evidence that mammalian brain sexual differentiation is under the influence of non-hormonal genetic factors.² Assuming the reproducibility of these findings, an obvious question concerns the relevance of these rodent studies to the process of sexual differentiation of the human brain and behavior. With regard to hormonal influences on the process, there exist important cross-species differences.³ The same might apply to non-hormonal genetic influences. A strategy followed in animal experimental research on sexual differentiation of brain and behavior has been to manipulate the level of hormones during steroid-sensitive periods of brain development and to observe effects in the expression of behaviors that are sex-dimorphic. In humans, researchers have relied on so-called “experiments of nature” (eg, disorders of sex development) to examine the effects of atypical prenatal sex hormone exposure on the process of psychosocial differentiation; specifically, formation of gender identity, gender role, and sexual orientation. In this study, the research strategy began by localizing the expression of Sry (a male-specific gene) in the brain of rodents. It was this approach that led the investigators to focus on the SN. Might reduced expression of Sry be responsible for thehigher incidence of Parkinson disease in men? However, the SN has not generally been a region of interest in the context of behavioral sex differences in animals or humans. One should, therefore, not be surprised if studies examining expression of Sry in the brain draw attention to regions not heretofore thought of as being responsible for sex-dimorphic behavior.

David E. Sandberg, PhD

References - (linked to )

Last Updated: 04/30/2008