Adrenal glands are the major organs releasing catecholamines and regulating our stress response. The mechanisms balancing generation of adrenergic chromaffin cells and protecting against neuroblastoma tumors are still enigmatic. Here we revealed that serotonin (5HT) controls the numbers of chromaffin cells by acting upon their immediate progenitor "bridge" cells via 5-hydroxytryptamine receptor 3A (HTR3A), and the aggressive HTR3Ahigh human neuroblastoma cell lines reduce proliferation in response to HTR3A-specific agonists. In embryos (in vivo), the physiological increase of 5HT caused a prolongation of the cell cycle in "bridge" progenitors leading to a smaller chromaffin population and changing the balance of hormones and behavioral patterns in adulthood. These behavioral effects and smaller adrenals were mirrored in the progeny of pregnant female mice subjected to experimental stress, suggesting a maternal-fetal link that controls developmental adaptations. Finally, these results corresponded to a size-distribution of adrenals found in wild rodents with different coping strategies.

Center for Neuroscience and Cognitive Systems Istituto Italiano di Tecnologia Rovereto Italy

Central European Institute of Technology Brno University of Technology Brno Czech Republic

Charité Universitätsmedizin Berlin 10117 Berlin Germany

Department of Experimental Biology Faculty of Science Masaryk University Brno Czech Republic

Department of Neuroimmunology Center for Brain Research Medical University Vienna Vienna Austria

Department of Neuroscience Karolinska Institute Stockholm Sweden

Department of Physiology and Pharmacology Karolinska Institute Stockholm Sweden

Federal state budgetary institution Research Zakusov Institute of Pharmacology Russian Academy of Sciences Moscow Russia

German Center for Cardiovascular Research Partner Site Berlin Germany

INSERM Paris Brain Institute Paris France

Institute for Biology University of Lübeck 23562 Lübeck Germany

International Clinical Research Center St Anne's University Hospital Brno Czech Republic

Koltsov Institute of Developmental Biology Russian Academy of Sciences Moscow Russia

Max Delbrück Center for Molecular Medicine 13125 Berlin Buch Germany

National Medical Research Center for Endocrinology Moscow Russia

Sechenov 1st Moscow State Medical University Moscow Russia

Severtsov Institute of Ecology and Evolution Russian Academy of Sciences Moscow Russia

Unit of Cell and Developmental Biology Department of Biology University of Pisa Pisa Italy

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