SEROTONIN LIMITS GENERATION OF CHROMAFFIN CELLS DURING ADRENAL ORGAN DEVELOPMENT

Adrenal gland is the major organ releasing catecholamines and regulating our stress response. The mechanisms balancing adrenal hormone-producing cells and protecting against neuroblastoma or other tumors are still enigmatic. Here we revealed that adrenergic chromaffin cells release serotonin (5HT), which acts upon their immediate progenitor “bridge” cells via 5-hydroxytryptamine receptor 3A (HTR3A). Consistently, the aggressive HTR3Ahigh human neuroblastoma cell lines reduce proliferation in response to HTR3A-specific agonists, suggesting the mechanism of anti-tumor protection. Physiological increase of 5HT in vivo caused prolongation of a cell cycle length in “bridge” progenitors leading to smaller chromaffin population and changing the balance of hormones and behavioral patterns in resulting adult rodents. These behavioral effects and smaller adrenals were mirrored in a progeny of pregnant females subjected to experimental stress, suggesting novel maternal-fetal link controlling developmental adaptations. Finally, these findings corresponded to a size-distribution of adrenals found in wild rodents with different coping strategies. Overall design: Wnt1-Cre+/-;R26RTomato+/+ E13.5 embryos prenatally treated with 5HTP (40 mg/kg) or vehicle (PBS) for control at E11.5 and E12.5 were harvested in iced cold PBS for smartseq2 sequencing