title: Ineffective erythropoiesis with reduced red blood cell survival in serotonin-deficient mice.
abstract: Serotonin (5-HT) has long been recognized as a neurotransmitter in the central nervous system, where it modulates a variety of behavioral functions. Availability of 5-HT depends on the expression of the enzyme tryptophan hydroxylase (TPH), and the recent discovery of a dual system for 5-HT synthesis in the brain (TPH2) and periphery (TPH1) has renewed interest in studying the potential functions played by 5-HT in nonnervous tissues. Moreover, characterization of the TPH1 knockout mouse model (TPH1(-/-)) led to the identification of unsuspected roles for peripheral 5-HT, revealing the importance of this monoamine in regulating key physiological functions outside the brain. Here, we present in vivo data showing that mice deficient in peripheral 5-HT display morphological and cellular features of ineffective erythropoiesis. The central event occurs in the bone marrow where the absence of 5-HT hampers progression of erythroid precursors expressing 5-HT(2A) and 5-HT(2B) receptors toward terminal differentiation. In addition, red blood cells from 5-HT-deficient mice are more sensitive to macrophage phagocytosis and have a shortened in vivo half-life. The combination of these two defects causes TPH1(-/-) animals to develop a phenotype of macrocytic anemia. Direct evidence for a 5-HT effect on erythroid precursors is provided by supplementation of the culture medium with 5-HT that increases the proliferative capacity of both 5-HT-deficient and normal cells. Our thorough analysis of TPH1(-/-) mice provides a unique model of morphological and functional aberrations of erythropoiesis and identifies 5-HT as a key factor for red blood cell production and survival.
authors.affiliation: Faculté de Médecine, Université Paris Descartes, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147, Hôpital Necker, 75743 Paris Cedex 15, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Amireault
authors.forename: Sarah
authors.initials: S
authors.lastname: Hatia
authors.forename: Elisa
authors.initials: E
authors.lastname: Bayard
authors.forename: Florence
authors.initials: F
authors.lastname: Bernex
authors.forename: Corinne
authors.initials: C
authors.lastname: Collet
authors.forename: Jacques
authors.initials: J
authors.lastname: Callebert
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Launay
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.forename: Elke
authors.initials: E
authors.lastname: Schneider
authors.forename: Jacques
authors.initials: J
authors.lastname: Mallet
authors.forename: Michel
authors.initials: M
authors.lastname: Dy
authors.forename: Francine
authors.initials: F
authors.lastname: Côté
mesh_terms: D000748:Anemia, Macrocytic / Q000150:complications / Q000201:enzymology / Q000473:pathology; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019587:Dietary Supplements; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D015672:Erythroid Precursor Cells / Q000378:metabolism / Q000473:pathology; D004920:Erythropoiesis / Q000187:drug effects; D007501:Iron / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000172:deficiency* / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D012806:Siderosis / Q000150:complications / Q000473:pathology; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D014365:Tryptophan Hydroxylase / Q000172:deficiency / Q000378:metabolism
chemical_list: D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D007501:Iron; D014365:Tryptophan Hydroxylase