Résumé :
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Communication n° 500. Serotonin (5-HT) controls multiple biological functions. While its importance in the nervous system is appreciated, its role at the periphery remains poorly understood. The rate-limiting step in 5-HT biosynthesis, is catalyzed by two isoforms of tryptophan hydroxylase, TPH1 and TPH2. Peripheral 5-HT is synthesized by TPH1 in the gastro-intestinal tract, is stored in blood platelets, participates in blood pressure, coagulation and hemostasis. Serotonin has also been suggested to regulate cardiovascular development through the 5-HT2B receptor. In view of the proposed functions of peripheral serotonin and to better understand the mechanisms by which it acts, we used a constitutive gene inactivation approach to ablate 5-HT function specifically in the periphery. The TPH1 mutant mice (TPH1-/-) were generated by targeting the bacterial lacZ reporter gene into the TPH1 locus under the control of the TPH1 promoter. Insertion of the marker into this locus made it possible to follow the activity of the TPH1 promoter in cells lacking the enzyme and to analyse the fate of these cells during mouse development. The biochemical, physiological, and histological consequences following disruption of the TPH1 gene include a dramatic reduction in peripheral 5-HT and functional alterations which can progressively lead to heart failure. Investigation of transverse sections of the heart showed no primary structural abnormalities indicative of a normal development. In order to provide a detailed expression analysis of TPH1 and TPH2 during mouse development, we performed in situ hybridization using specific non-overlapping probes for both genes. This approach yields novel information on areas expressing the two TPH isoforms. The expression of TPH2 is neuro-specific and occurs as early as E10.5 in the ventral most neuroepithelial domain of the hindbrain, while production of peripheral 5-HT has been observed on E9.5 in the yolk sac. Our data suggest that the low level of circulating 5-HT in TPH1-/- animals is sufficient for development and viability of the mouse embryo. Specifically no developmental abnormality was observed either in skeletal or cardiac muscles. The serotonin level is, however, critical to maintain normal cardiac function in the adult animal.
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