Serotonin 2B receptor is required for heart development.
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.
Nebigil
C G
CG
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, Illkirch, France.
Choi
D S
DS
Dierich
A
A
Hickel
P
P
Le Meur
M
M
Messaddeq
N
N
Launay
J M
JM
Maroteaux
L
L
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D002455:Cell Division; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005313:Fetal Death; D017353:Gene Deletion; D018734:Genes, erbB-2 / Q000235:genetics; D006321:Heart / Q000196:embryology* / Q000503:physiopathology; D006330:Heart Defects, Congenital / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D020962:Heterotrimeric GTP-Binding Proteins; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin