Gene regulation by gonadal hormone receptors underlies brain sex differences

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.