Estrogen receptor alpha (ERa) orchestrates sexual differentiation in the mouse brain by establishing male-biased neuron types and activating a sustained male-biased gene expression program. Sex differences in gene expression are primarily driven by hormonal activation of neuronal steroid receptors, with puberty acting as a critical period for sexual differentiation.

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This study provides a comprehensive and detailed analysis of the genomic targets of ERa in the brain, revealing its role in brain sexual differentiation. The methodology is rigorous, using multiple techniques to validate findings. While there are some limitations, such as the limited number of replicates in some experiments, the overall quality of the research is high.