Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function

doi:10.1073/pnas.2233056100

Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function

^*Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7091 et Institut Fédératif de Recherche 70 (Neurosciences), Bâtiment CERVI, Hôpital de la Pitié-Salpêtrière, 83, Boulevard de l'Hôpital, 75013 Paris, France; ^†Institut de Myologie et Institut Fédératif de Recherche 14 (Coeur, Muscle, Vaisseaux), Institut National de la Santé et de la Recherche Médicale Unité 582, Centre Hospitalier Universitaire Pitié-Salpêtrière, 47, Boulevard de l'Hôpital, 75013 Paris, France; ^‡Laboratoire de Neuropsychopharmacologie, Institut National de la Santé et de la Recherche Médicale, Unité 288, et Institut Fédératif de Recherche 70 (Neurosciences), Centre Hospitalier Universitaire Pitié-Salpêtrière, 91, Boulevard de l'Hôpital, 75013 Paris, France; ^§Genomic Imprinting Group, Génétique, Departement Dévéloppement et Pathologie Moléculaire, Institut Cochin, 24, Rue du Fbg St Jacques, 75014 Paris, France; and ^¶Service de Pharmacologie, Unité Propre de Recherche de l'Enseignement Superieur 2391 et Institut Fédératif de Recherche 14 (CMV), Centre Hospitalier Universitaire Pitié-Salpêtrière, 47, Boulevard de l'Hôpital, 75013 Paris, France

Edited by Floyd E. Bloom, The Scripps Research Institute, La Jolla, CA, and approved September 4, 2003 (received for review May 21, 2003)

Abstract

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.

Footnotes

↵ ∥ To whom correspondence should be addressed. E-mail: mallet{at}infobiogen.fr.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: 5-HT, serotonin (5-hydroxytryptamine); TPH, tryptophan hydroxylase; ES, embryonic stem; β-gal, β-galactosidase; bpm, beats per minute; LV, left ventricle; ISH, in situ hybridization.