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Abstract:
Prenatal development affects adult health. Exposures to a variety of prenatal environ-mental factors have important effects on fetal development and, in turn, are extensively associated with neurobehavioral, structural and functional phenotypes after birth. Developmental processes are in part promoted by orchestrated levels of glucocorticoids, which are steroid hormones involved in fetal organ maturation. Glucocorticoids also mediate the hormonal stress response of the organism as part of the hypothalamic-pituitary-adrenal axis. During pregnancy levels of glucocorticoids outside of the normal range, either due to maternal pathology including stress-related psychiatric disorders or to antenatal synthetic glucocorticoid treatments, have been associated with altered brain structural and neurobehavioral phenotypes after birth. Interestingly, developmental time-windows seem to interplay with the exposure to influence the direction of post-natal phenotypes. Exposures later in gestation are mainly associated with adverse out-comes while exposures earlier in gestation are additionally associated with potentially beneficial outcomes. While many studies have investigated the effects of glucocorticoids on late developmental time-windows, so far little evidence is available on their effects on early human cortical development and especially during the neurogenic period, which is when neurons are produced. Thus, the potential cellular and molecular underpinnings of the timing dependent divergent effects of glucocorticoids on postnatal phenotypes are not known.
To investigate these processes in a complex model of early human neurodevelopment that is reactive to environmental stimuli, I used induced Pluripotent Stem Cells-derived 3-dimensional cerebral organoids and combined them with in vivo mouse neurodevelopment. I found that application of glucocorticoids during neurogenesis increases neurogenic processes that are enriched in species with a gyrified brain, like humans, while are rare in species with a smooth brain, like rodents. These processes contribute to the increased neuronal production and cortical expansion seen in gyrencephalic species. More specifically, at the molecular level this effect is mediated by the glucocorticoid receptor, a transcription factor, which in turn activates ZBTB16 by altering its methylation landscape in specific DNA regulatory elements. Subsequently ZBTB16, a transcription factor itself, increases the expression of PAX6, a key driver of neurogenesis, by activating its promoter. This results in increased numbers of progenitor cells expressing PAX6 and EOMES (a marker of more mature progenitors) in the basal regions of the germinal zones in both organoids and mice. PAX6- and EOMES- positive progenitors are enriched in gyrified species while they are rare in species with smooth brains. The increased numbers of these highly proliferative and neurogenic progenitors lead to an extended neurogenic period and ultimately to increased production of deep layer neurons (BCL11B- positive). Finally, the altered cellular architecture due to glucocorticoids and ZBTB16 potentially mediates beneficial postnatal outcomes as indicated by causal associations with higher educational attainment and increased postnatal cortical thick-ness.
This work highlights the importance of early neurodevelopment and specifically of the neurogenic period as a sensitive time-window for glucocorticoid effects. In addition, the molecular and cellular mechanisms as well as the pathways identified could have pro-found implications for our understanding of glucocorticoid effects during early brain development that potentially mediate postnatal outcomes.
