Before hormones: early sex-specific mechanisms shaping nervous system development, function, and postnatal disease susceptibility.

Brain development requires precise spatiotemporal regulation of gene expression and molecular processes to establish healthy and functional neural circuits. Traditionally, sex differences in brain development have been attributed primarily to gonadal differentiation and the subsequent actions of sex hormones on developmental systems during fetal life. However, these observations alone cannot fully explain the spectrum of sex biases seen in diverse neurodevelopmental, neuropsychiatric, and neurological disorders. In this mini review, we discuss the current evidence supporting the early embryonic origins of sex differences in brain development, with an emphasis on sex chromosome-driven transcriptional regulation, X chromosome inactivation dynamics, and sex-biased gene expression, which precede hormone-dependent developmental signaling. We present recent advances using omics technologies and computational approaches that have revealed widespread sex-biased differences in gene expression, chromatin regulation, dosage compensation, alternative splicing, and transcriptional activity during preimplantation and early embryonic development. These results are derived from available human datasets, but also include data from experimental models, including Drosophila melanogaster, and elaborate on the translational application of these findings in humans during normal neurodevelopment and in disease states. Collectively, these findings support a model in which sex-specific features of brain development emerge from the earliest stages of embryogenesis and continue to shape brain structure and function throughout life. Furthermore, they emphasize the necessity of including sex as a variable in research and medicine.