Genes in the Azoospermia Factor A Region of the Y Chromosome Show Sexual Dimorphism in Rat Brain Prior to Gonadal Sex Differentiation
Abstract BackgroundThe classical concept of brain sex differentiation suggests that steroid hormones released from the gonads program male and female brains differently. However, several studies indicate that steroid hormones are not the only determinant of brain sex differentiation and that genetic differences could also be involved.MethodsIn this study, we have performed RNA sequencing of rat brains at embryonic days 12 (E12), E13, and E14. The aim was to identify differentially expressed genes between male and female rat brains during early development. ResultsAnalysis of genes expressed with the highest sex differences showed that Xist was highly expressed in females having XX genotype with an increasing ratio over time. Analysis of genes expressed with the highest male expression identified three main genes. At E12, two genes located in the azoospermia factor A (AZFa) region on the Y chromosome were highly expressed in males. These were Ddx3y (1552-fold higher in males) and Kdm6c (147-fold higher in males). The expression of Kdm6c, but not Ddx3y, remained high at both E13 and E14. In qRT-PCR analysis, these two genes were highly expressed in all the stages in male brain. In addition to these genes, one of the several copies of Sry in the rat genome, Sry4, showed a high expression in the male brains at all three time points. At all three time points several other genes were also found to show sex bias, but with lower differences in gene expression. ConclusionThe observed sex-specific expression of genes at early development suggests that the rat brain is sexually dimorphic prior to gonadal action on the brain and identifies the AZFa region genes as a possible contributor to male brain development.