Brain-synthesized estrogens regulate cortical migration in a sexually divergent manner.

Estrogens play an important role in brain development when they have been implicated in controlling various cellular processes. Several lines of evidence have been presented showing that estrogens can be synthesised locally within the brain. Studies have demonstrated that aromatase, the enzyme responsible for the conversion of androgens to estrogens, is expressed during early development in both male and female cortices. Furthermore, 17beta-estradiol has been measured in fetal brain tissue from multiple species. 17beta-estradiol regulates neural progenitor proliferation as well as the development of early neuronal morphology. However, what role locally derived estrogens play in regulating cortical migration and moreover, whether these effects are the same in male and females is unknown. Here we investigated the impact of knockdown expression of Cyp19a1, which encodes aromatase, between embryonic day (E) 14.5 and postnatal day 0 (P0) had on neural migration within the cortex. Aromatase was expressed in the developing cortex of both sexes, but at significantly higher levels in male than female mice. Under basal conditions, no obvious differences in cortical migration between male and female mice were observed. However, knockdown of Cyp19a1 resulted in an increase in cells within the cortical plate, and a concurrent decrease in the subventricular zone/ventricular zone in P0 male mice. Interestingly, the opposite effect was observed in females, who displayed a significant reduction in cells migrating to the cortical plate. Together these findings indicate that brain-derived estrogens regulate radial migration through distinct mechanisms in males and females.