Sex-differential expression of genes and microRNAs in the developing brain

Szakats SK and Wilson MJ

University of Otago, PO Box 56, Dunedin 9054, New Zealand.

Biological sex contributes to many pathologies. Investigating sex differences is therefore a powerful strategy for identifying mechanisms underlying idiopathic disorders with a sex bias, including neurodevelopmental disorders such as ADHD, schizophrenia and autism. Regulation of gene expression by sex may alter development of the brain, thus we investigated sex-differential gene expression in the embryonic (E15.5) mouse brain. Given the importance of microRNAs (miRNAs) in regulating developmental processes, we also postulated that their expression may differ between the sexes during neurodevelopment. RNA sequencing identified 98 genes with significantly different expression between males and females (n=3/sex, p adj.<0.05), while small RNA sequencing identified 67 sex-differentially expressed miRNAs (n=3/sex, FDR<0.05). RT-qPCR has confirmed differential expression several genes and miRNAs, and in situ hybridisation has been used to investigate spatial expression patterns of Aff2, Dicer1, Eif2s3y and miR-10a/b-5p from this data set. Finally, gene ontology analysis to compare over-represented pathways targeted by upregulated genes and miRNA target genes in males compared to females reveals sex differences in pathways with various developmental and neurological functions. Future experiments aim to establish how sex differences in the regulation of gene expression are induced, and identify how those genes and miRNAs identified to be sex dimorphic contribute to sex differences in neurodevelopmental disorders.