Sex-biased gene and microRNA expression in the developing mouse brain is associated with neurodevelopmental functions and neurological phenotypes

Abstract Background: Sex differences pose a challenge and an opportunity in biomedical research. Understanding how sex chromosomes and hormones affect disease-causing mechanisms will shed light on the mechanisms underlying predominantly idiopathic sex-biased neurodevelopmental disorders such as ADHD, schizophrenia and autism. Gene expression is a crucial conduit for the influence of sex on developmental processes; therefore, this investigation focused on sex differences in gene expression and regulation of gene expression. Mounting interest in microRNAs (miRNAs), small, non-coding RNAs for their contribution to normal and pathological neurodevelopment prompted us to test how miRNA expression differs between the sexes in the developing brain. Methods: High-throughput sequencing approaches were used to identify transcripts, including miRNAs, showing significantly different expression between male and female brains at day 15.5 of development (E15.5). Results: Robust sex differences were identified for a portion of genes and miRNAs, confirming the influence of biological sex on RNA in this context. Many miRNAs showing the greatest differences between males and females have established roles in neurodevelopment, implying that sex-biased expression could drive sex differences in developmental processes. In addition to highlighting sex differences for individual miRNAs, gene ontology analysis suggests several broad categories in which sex-biased RNAs might be acting to establish sex differences in the embryonic mouse brain. Finally, mining publically available SNP data indicated that some sex-biased miRNAs reside near genomic regions associated with neurodevelopmental disorders. Conclusions: Together, these findings reinforce the importance of cataloguing sex differences in molecular biology research and highlight genes, miRNAs and pathways of interest that may be important for sexual differentiation of the mouse and possibly the human brain.