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

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 ␤-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 ␤-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. S erotonin (5-hydroxytryptamine, 5-HT) was discovered in blood as a vasoconstrictor of large vessels (1). Subsequently, it has been found in the gastrointestinal tract as a contractile substance identical with enteramine (2), in the CNS as a neurotransmitter (3), and in the pineal gland as an intermediate in the synthesis of melatonin, the neurohormone implicated in the circadian rhythmicity of physiological functions (4). 5-HT is detected early during brain development, suggesting its involvement in neuronal proliferation, migration, and differentiation (5). 5-HT modulates a variety of behavioral functions, including regulation of sleep͞wakefulness, appetite, nociception, mood, stress, and maternal or sexual behavior (6). Altered regulation of 5-HT in human affects behavioral traits and personality disorders, such as impulsive aggression, manic depressive illness, anxiety and alcoholism, and neurological conditions, such as migraine (7-10).About 95% of the 5-HT in the periphery is in the gastrointestinal tract (11), where it initiates responses as diverse as nausea, intestinal secretion, and peristaltis and has been implicated in gastroenteric diseases, such as irritable bowel syndrome (12). The 5-HT originating from the gastrointestinal tract is stored in blood platelets and participates in blood coagulation and pressure and in homeostasis. In the heart, an increased 5-HT availability has been shown to produce arrhythmia, leading to heart block or to valvular fibroplasia (13). 5-HT has also been suggested to regulate cardiovascular development (14). Recently, disruption of 5HT-2B receptor revealed a role for 5-HT by means of...

Serotonin in pre-implantation mouse embryos is localized to the mitochondria and can modulate mitochondrial potential

“…In this context, it is interesting to note that embryonic stem cells, which are derivatives of blastocysts, have been suggested to have a default Serotonin in mitochondria in mouse embryos neuronal fate (Tropepe et al 2001). Interestingly, deletion of Tph1 in the mouse does not seem to affect early embryogenesis drastically though it does exhibit specific physiological phenotypes in later stages of development (Cote et al 2003(Cote et al , 2004. There is as yet no published report of a Tph2 knockout mouse.…”

Genetic Models of Serotonin (5‐HT) Depletion: What do They Tell Us About the Developmental Role of 5‐HT?

“…The Tph1 À/À mice showed a 90% reduction of circulating 5-HT in the blood and in the gut, but had normal levels of 5-HT in the brain (Cote et al, 2003;. The Tph1 À/À mice appeared to develop normally when they were born from heterozygote mothers.…”

“…1). Tph1 is expressed in the pineal gland, the enterochromaffin cells (Cote et al, 2003), the beta pancreatic cells, and the other peripheral tissues which produce 5-HT ( Fig. 1).…”

Severe Serotonin Depletion after Conditional Deletion of the Vesicular Monoamine Transporter 2 Gene in Serotonin Neurons: Neural and Behavioral Consequences

“…In situ hybridization experiments were performed as described previously (Bally-Cuif and Wassef, 1994). The TPH2 c-DNA plasmid described previously (Cote et al, 2003) was donated by P Ravassard (CRICM, UPMC, Paris).…”