Disruption of the Nonneuronal tph1 Gene Demonstrates the Importance of Peripheral Serotonin in Cardiac Function

• Published in: Proceedings of the National Academy of Sciences - PNAS 2003-11, Vol.100 (23), p.13525-13530
• Main Authors: Côté, Francine, Thévenot, Etienne, Fligny, Cécile, Fromes, Yves, Darmon, Michèle, Ripoche, Marie-Anne, Bayard, Elisa, Hanoun, Naima, Saurini, Françoise, Lechat, Philippe, Dandolo, Luisa, Hamon, Michel, Mallet, Jacques, Vodjdani, Guilan
• Format: Article
• Language: English
• Subjects: Alleles; Animals; beta-Galactosidase - metabolism; Biological Sciences; Chromaffin Cells - metabolism; Chromatography, High Pressure Liquid; Embryo, Mammalian - cytology; enterochromaffin cells; Genetics; Genotype; Heart; Humans; Hydroxyindoleacetic Acid - metabolism; Immunohistochemistry; In Situ Hybridization; Mallets; Medical research; Messenger RNA; Mice; Mice, Mutant Strains; Mice, Transgenic; Models, Genetic; Mutation; Myenteric Plexus - metabolism; Myocardium; Myocardium - cytology; Neurons; Phenotype; Pineal gland; Raphe nuclei; Raphe Nuclei - metabolism; Receptors; RNA, Messenger - metabolism; Serotonin - metabolism; Serotonin - physiology; Serotonin receptors; Stem Cells - metabolism; Tissue Distribution; tph1 gene; tph2 gene; tryptophan hydroxylase; Tryptophan Hydroxylase - genetics; Tryptophan Hydroxylase - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2233056100

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 β-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 β-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.