Sex chromosome effects on aromatase expression and regulation in mouse developing brain

CAMBIASSO, M.J.; CISTERNAS, C.D.

Turin

Congreso; 9th International Meeting STEROIDS and NERVOUS SYSTEM; 2017

Duringthe critical period of sexual differentiation there are sex differences in brainaromatase expression that are time and regionally specific. Some of these sexdifferences cannot be explained by organizational actions of gonadal hormonesbecause they occur before exposition to testosterone in utero. We have assessed aromatase expression at embryonic day 16 and we have confirmeda neuronal pattern of expression in the stria terminalis and some regions of amygdala.To analyze the roleof sex chromosome complement in sexually dimorphic expression of aromatase weused the Four Core Genotype (FCG) mouse model, in which the effect of gonadal sex and sexchromosome complement is dissociated. Our results indicate that independent ofgonadal sex (testes-ovaries) XY brain show a higher expression of aromatase(protein and mRNA) in the bed nucleus of stria terminalis and anterior amygdalaarea at E16 than XX brain embryos. We next used primary neuronal cultures ofanterior amygdala to evaluate whether the differential Cyp19a1 expression between genotypes could be regulated by gonadal hormonesand our results show that 17β-estradiol (E2) or dihydrotestosterone (DHT) in vitro increases aromatase expressionin amygdala neurons from XX embryos, but not in those derived from XY embryoscompensating sex chromosome-induced sex differences in Cyp19a1 expression. As E2and DHT regulate transcription of target genes via estrogen or androgenreceptors we studied if aromatase regulation involves a change in steroidreceptor expression. Our results show that in a way that resembles aromataseexpression, amygdala neurons from XY brain have a higher expression of ERβmRNA than XX neurons and E2 or DHT hormonal treatment increases ERβmRNA only in XX neurons (male and female) but did not regulate ERα and ARexpression. Furthermore, the use of agonists and antagonists of estrogenreceptors (ERα and ERβ) indicate that aromatase regulation in XX neurons is viaERβ. Based on the results we conclude that sex chromosome complement is the mainfactor that determines expression of aromatase and their regulation by gonadalhormones. Given that it is a key enzyme necessary for organizational actions ofgonadal testosterone these findings imply that genetic and gonadal factorsinteract in the generation of sex differences in some structures of thedeveloping rodent brain. As several X/Ylinked genes encoding transcriptionalregulator proteins have the potential to mediate chromatin changes and regulateautosomal gene expression further studies are needed to determine if sexdifferences in brain expression of aromatase and ERβ at E16 depends on particular epigenetic marks in XX and XY embryos.