Sex-biased microRNA expression in the developing mouse brain: Multiple mechanisms driving its origin.

The developing mouse brain exhibits sex-biased microRNA (miRNA) expression driven by complex genetic, regulatory, and hormonal mechanisms. This study explored six hypotheses contributing to sex-biased miRNA expression in the E15.5 mouse brain: Y-chromosome linkage, escape from X to inactivation, regulation by sex-biased transcription factors, co-regulation of sex-biased miRNAs with their host genes, interaction of biological sex and miRNA processing, and transcriptional regulation by the estrogen receptor (ER) pathway. Evidence supports all of the mechanisms tested, except Y-linkage, as contributors to sex-biased miRNA expression. The combination of genetic factors, regulatory mechanisms, and hormonal influences reinforces the notion that miRNA expression in the developing brain has evolved to drive sex-related differences. Understanding these mechanisms is crucial for elucidating the observed sex disparities in various aspects of neurodevelopment and etiology of neurodevelopmental disorders.