[Abnormal cardiac activity in mice in the absence of peripheral serotonin synthesis].
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. Based on the study of a mutant mouse in which the TPH1 gene has been inactivated by replacement of the beta-galactosidase gene, we established that the neuronal TPH2 is expressed in neurons of the raphe nuclei and of the myenteric plexus, whereas the non-neuronal TPH1, as detected by beta-galactosidase expression, is expressed in the pineal gland and the enterochromaffin cells. Anatomic examination of the mutant mice revealed larger heart sizes as compared to wild-type. Histologic investigations indicated that the primary structure of the heart muscle is not affected. Hemodynamic analyses in mutant animals demonstrated abnormal cardiac activity which ultimately leads to heart failure. This is the first report linking loss of TPH1 gene expression, and thus of peripheral 5-HT, to a cardiac dysfunction phenotype. The TPH1 -/- mutant may be a valuable model for investigating cardiovascular dysfunction such as those observed in human heart failure.
Côté
Francine
F
Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, CNRS UMR7091, Bâtiment CERVI, Hôpital de la Pitié-Salpêtrière, 83, boulevard de l'Hôpital, 75013 Paris, France.
Fligny
Cécile
C
Mallet
Jacques
J
Vodjdani
Guilan
G
D000483:Alleles; D000818:Animals; D006332:Cardiomegaly / Q000150:complications / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D004759:Enterochromaffin Cells / Q000201:enzymology; D018390:Gene Targeting; D006333:Heart Failure / Q000209:etiology; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009197:Myenteric Plexus / Q000201:enzymology; D009419:Nerve Tissue Proteins / Q000502:physiology; D009928:Organ Specificity; D010641:Phenotype; D010870:Pineal Gland / Q000201:enzymology; D011903:Raphe Nuclei / Q000201:enzymology; D012701:Serotonin / Q000096:biosynthesis / Q000172:deficiency*; D014365:Tryptophan Hydroxylase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D012701:Serotonin; C487801:Tph1 protein, mouse; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase