Gene regulatory mechanisms underlying sex differences in brain development and psychiatric disease

The sexual differentiation of the mammalian nervous system requires the precise coordination of the temporal and spatial regulation of gene expression in diverse cell types. Sex hormones act at multiple developmental time points to specify sex-typical differentiation during embryonic and early development and to coordinate subsequent responses to gonadal hormones later in life by establishing sex-typical patterns of epigenetic modifications across the genome. Thus, mutations associated with neuropsychiatric conditions may result in sexually dimorphic symptoms by acting on different neural substrates or chromatin landscapes in males and females. Finally, as stress hormone signaling may directly alter the molecular machinery that interacts with sex hormone receptors to regulate gene expression, the contribution of chronic stress to the pathogenesis or presentation of mental illness may be additionally different between the sexes. Here, we review the mechanisms that contribute to sexual differentiation in the mammalian nervous system and consider some of the implications of these processes for sex differences in neuropsychiatric conditions.