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...

The early appearance of serotonin and its receptors during prenatal development, together with the many effects serotonin exerts during CNS morphogenesis, strongly suggest that serotonin influences the development and maturation of the mammalian brain before it becomes a neuromodulator/neurotransmitter. Sites of early serotonin biosynthesis, however, have not been detected in mouse embryos or extraembryonic structures, suggesting that the main source of serotonin could be of maternal origin. This hypothesis was tested by using knockout mice lacking the tph1 gene, which is responsible for the synthesis of peripheral serotonin. Genetic crosses were performed to compare the phenotype of pups born from homozygous and heterozygous mothers. Observations provide the first clear evidence that (i) maternal serotonin is involved in the control of morphogenesis during developmental stages that precede the appearance of serotonergic neurons and (ii) serotonin is critical for normal murine development. Most strikingly, the phenotype of tph1؊/؊ embryos depends more on the maternal genotype than on that of the concepti. Consideration of the maternal genotype may thus help to clarify the influence of other genes in complex diseases, such as mental illness.genotype/phenotype ͉ tph1 knockout mice ͉ tryptophan hydroxylase S erotonin participates in a wide range of physiological systems including the control of gastrointestinal motility and secretion, cardiovascular regulation, hemostatic processes, the regulation of circadian rhythms, the sleep-wake cycle, perception of pain, appetite, manifestation of nausea, and sexual behavior. Accumulating in vitro evidence also indicates that serotonin signaling participates in the regulation of development in many animal phyla before the onset of neurogenesis. Serotonin thus plays a role in development before it acts as a neurotransmitter (1-3). Serotonin affects craniofacial, gastrointestinal, and cardiovascular morphogenesis in chicken, rat, and mouse; these effects are often mediated by the serotonin 2B receptor (4-7). Altogether, the presence of serotonin, its receptors, and transporter during development and the ability of compounds that modulate serotonergic signaling to interfere with development suggest that serotonin functions as a humoral morphogen (8-10). Sites of early serotonin biosynthesis, however, have not been detected in embryos or extraembryonic structures of the mouse. It has therefore been assumed that the main source of serotonin is maternal (11).We have generated a mouse line deficient in peripheral serotonin biosynthesis. Targeted disruption of the tryptophan hydroxylase 1 (tph1) gene resulted in levels of circulating serotonin that are only 3-15% of those of normal mice. The null mutants (tph1Ϫ/Ϫ) from heterozygous crosses are viable and display no gross anatomical abnormalities, but they develop cardiac insufficiency in adulthood (12). The tph1Ϫ/Ϫ mice thus provide a convenient tool to address the developmental role of maternal serotonin. tph1-null females were bred...