Serotonin 2B receptor is required for heart development

Serotonin 2B receptor is required for heart development

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université L. Pasteur de Strasbourg, BP 163, 67404 Illkirch Cedex, France

Edited by Robert J. Lefkowitz, Duke University Medical Center, Durham, NC, and approved June 13, 2000 (received for review March 20, 2000)

Abstract

Several lines of evidence suggest that the serotonin (5-hydroxytryptamine, 5-HT) regulates cardiovascular functions during embryogenesis and adulthood. 5-HT binds to numerous cognate receptors to initiate its biological effects. However, none of the 5-HT receptor disruptions in mice have yet resulted in embryonic defects. Here we show that 5-HT_2B receptor is an important regulator of cardiac development. We found that inactivation of 5-HT_2B gene leads to embryonic and neonatal death caused by heart defects. 5-HT_2B mutant embryos exhibit a lack of trabeculae in the heart and a specific reduction in the expression levels of a tyrosine kinase receptor, ErbB-2, leading to midgestation lethality. These in vivo data suggest that the Gq-coupled receptor 5-HT_2B uses the signaling pathway of tyrosine kinase receptor ErbB-2 for cardiac differentiation. All surviving newborn mice display a severe ventricular hypoplasia caused by impaired proliferative capacity of myocytes. In adult mutant mice, cardiac histopathological changes including myocyte disarray and ventricular dilation were consistently observed. Our results constitute genetic evidence that 5-HT via 5-HT_2B receptor regulates differentiation and proliferation of developing and adult heart. This mutation provides a genetic model for cardiopathy and should facilitate studies of both the pathogenesis and therapy of cardiac disorders in humans.

Footnotes

↵ * Present address: Department of Neurology, Gallo Center, University of California, San Francisco, CA 94110.
↵ † CR C. Bernard “Pathologie expérimentale et communications cellulaires” IFR 6 Hôpital Lariboisière, Service de Biochimie, 2 rue Ambroise Paré, 75475 Paris Cedex 10, France.
↵ ‡ To whom reprint requests should be addressed. E-mail: lucm{at}titus.u-strasbg.fr.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

CNS,

central nervous system;

dpc,

day postcoitum;

ES,

embryonic stem;

5-HT,

serotonin (5-hydroxytryptamine);

TEM,

transmission electron microscopy