Abstract
BackgroundIt is well-established that organizational effects of sex steroids during early development are fundamental for sex-typical displays of, for example, mating and aggressive behaviors in rodents and other species. Male and female brains are known to differ with respect to neuronal morphology in particular regions of the brain, including the number and size of neurons, and the density and length of dendrites in nuclei of hypothalamus and amygdala. The aim of the present study was to use global proteomics to identify proteins differentially expressed in hypothalamus/amygdala during early development (postnatal day 8) of male, female and conditional androgen receptor knockout (ARNesDel) male mice, lacking androgen receptors specifically in the brain. Furthermore, verification of selected sexually dimorphic proteins was performed using targeted proteomics.ResultsOur proteomic approach, iTRAQ, allowed us to investigate expression differences in the 2998 most abundantly expressed proteins in our dissected tissues. Approximately 170 proteins differed between the sexes, and 38 proteins between ARNesDel and control males (p < 0.05). In line with previous explorative studies of sexually dimorphic gene expression we mainly detected subtle protein expression differences (fold changes <1.3). The protein MARCKS (myristoylated alanine rich C kinase substrate), having the largest fold change of the proteins selected from the iTRAQ analyses and of known importance for synaptic transmission and dendritic branching, was confirmed by targeted proteomics as differentially expressed between the sexes.ConclusionsOverall, our results provide solid evidence that a large number of proteins show sex differences in their brain expression and could potentially be involved in brain sexual differentiation. Furthermore, our finding of a sexually dimorphic expression of MARCKS in the brain during development warrants further investigation on the involvement in sexual differentiation of this protein.
Highlights
It is well-established that organizational effects of sex steroids during early development are fundamental for sex-typical displays of, for example, mating and aggressive behaviors in rodents and other species
In the present study, we were able to identify a total of 2998 proteins in hypothalamus and amygdala of neonatal male, female and ARNesDel male mice
After excluding proteins lacking expression values for more than three samples, 2273 proteins were compared between the sexes and 2293 proteins were compared between ARNesDel males and male controls
Summary
It is well-established that organizational effects of sex steroids during early development are fundamental for sex-typical displays of, for example, mating and aggressive behaviors in rodents and other species. There are striking sex differences in many aspects of behaviors, not least in social behaviors such as mating and displaying of aggression [1]. Estrogens through the ERs are essential for establishing male sexual and territorial behaviors whereas testosterone through the AR rather modulates the extent of these behavioral displays [1, 8]. These steroid receptors are ligand-activated transcription factors, and through the influence on the gene transcription they have the capability to regulate the expression levels of many different proteins. The sex steroids can bind to membrane bound receptors and thereby activate signal transduction pathways associated with changes in cell physiology [9]
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