Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function.
Serotonin (5-HT) controls a wide range of biological functions. In the brain, its implication as a neurotransmitter and in the control of behavioral traits has been largely documented. At the periphery, its modulatory role in physiological processes, such as the cardiovascular function, is still poorly understood. The rate-limiting enzyme of 5-HT synthesis, tryptophan hydroxylase (TPH), is encoded by two genes, the well characterized tph1 gene and a recently identified tph2 gene. In this article, based on the study of a mutant mouse in which the tph1 gene has been inactivated by replacement with the beta-galactosidase gene, we establish that the neuronal tph2 is expressed in neurons of the raphe nuclei and of the myenteric plexus, whereas the nonneuronal tph1, as detected by beta-galactosidase expression, is in the pineal gland and the enterochromaffin cells. Anatomic examination of the mutant mice revealed larger heart sizes than in wild-type mice. Histological investigation indicates that the primary structure of the heart muscle is not affected. Hemodynamic analyses demonstrate abnormal cardiac activity, which ultimately leads to heart failure of the mutant animals. This report links loss of tph1 gene expression, and thus of peripheral 5-HT, to a cardiac dysfunction phenotype. The tph1-/- mutant may be valuable for investigating cardiovascular dysfunction observed in heart failure in humans.
Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, CNRS, Unité Mixte de Recherche 7091 et Institut Fédératif de Recherche 70, Hôpital de la Pitié-Salpêtrière, Paris, France.
Francine
F
Côté
Etienne
E
Thévenot
Cécile
C
Fligny
Yves
Y
Fromes
Michèle
M
Darmon
Marie-Anne
MA
Ripoche
Elisa
E
Bayard
Naima
N
Hanoun
Francoise
F
Saurini
Philippe
P
Lechat
Luisa
L
Dandolo
Michel
M
Hamon
Jacques
J
Mallet
Guilan
G
Vodjdani
D000483:Alleles; D000818:Animals; D019439:Chromaffin Cells / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004622:Embryo, Mammalian / Q000166:cytology; D005838:Genotype; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008957:Models, Genetic; D009154:Mutation; D009197:Myenteric Plexus / Q000378:metabolism; D009206:Myocardium / Q000166:cytology*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D011903:Raphe Nuclei / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D013234:Stem Cells / Q000378:metabolism; D014018:Tissue Distribution; D014365:Tryptophan Hydroxylase / Q000235:genetics* / Q000502:physiology; D001616:beta-Galactosidase / Q000378:metabolism
D012333:RNA, Messenger; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D014365:Tryptophan Hydroxylase; D001616:beta-Galactosidase