Several lines of evidence suggest that the serotonin (5-hydroxytryptamine, 5-HT) regulates cardiovascular functions during embryogenesis and adulthood. 5-HT binds to numerous cognate receptors to initiate its biological effects. However, none of the 5-HT receptor disruptions in mice have yet resulted in embryonic defects. Here we show that 5-HT 2B receptor is an important regulator of cardiac development. We found that inactivation of 5-HT2B gene leads to embryonic and neonatal death caused by heart defects. 5-HT 2B mutant embryos exhibit a lack of trabeculae in the heart and a specific reduction in the expression levels of a tyrosine kinase receptor, ErbB-2, leading to midgestation lethality. These in vivo data suggest that the Gq-coupled receptor 5-HT 2B uses the signaling pathway of tyrosine kinase receptor ErbB-2 for cardiac differentiation. All surviving newborn mice display a severe ventricular hypoplasia caused by impaired proliferative capacity of myocytes. In adult mutant mice, cardiac histopathological changes including myocyte disarray and ventricular dilation were consistently observed. Our results constitute genetic evidence that 5-HT via 5-HT2B receptor regulates differentiation and proliferation of developing and adult heart. This mutation provides a genetic model for cardiopathy and should facilitate studies of both the pathogenesis and therapy of cardiac disorders in humans.neuregulin ͉ knockout ͉ proliferation ͉ transactivation S erotonin (5-hydroxytryptamine) (5-HT) first isolated as a vasoconstrictor from blood was later identified in the central nervous system (CNS). It is found in three main areas of the body: the intestinal wall, platelets, and CNS. The functions of 5-HT in CNS as a neurotransmitter are numerous and appear to involve control of appetite, sleep, memory and learning, temperature regulation, mood, behavior (including sexual and hallucinogenic behavior), and endocrine regulation (1). Peripherally, 5-HT, which is stored in platelets, appears to play a major role in homeostasis, blood pressure regulation, cardiovascular functions (2), motility of the gastrointestinal tract (3), and carcinoid tumor pathology (4). Independently of its location in adults, 5-HT also has been detected during zygotic cleavage divisions, gastrulation and neurulation in embryos of sea urchins, frogs, chicken, and Drosophila. The presence of 5-HT and its receptors in early embryogenesis and the ability of 5-HTspecific pharmacological agents (5) to interfere with embryonic development suggested that early embryos use 5-HT before the onset of neurogenesis to regulate cell proliferation and͞or morphogenetic movements (6, 7). Furthermore, 5-HT has been suspected for years to regulate craniofacial and cardiovascular morphogenesis: In embryos grown in the presence of either a high concentration of 5-HT or 5-HT-specific reuptake inhibitors, a decreased proliferation of myocardium, cardiac mesenchyme, and endothelium has been reported, indicating that 5-HT may regulate proliferation in the embryonic heart (8).Th...

In this paper, we present evidence that activation of 5-hydroxytryptamine 2B (5-HT2B) receptors by serotonin (5-HT) leads to cell-cycle progression through retinoblastoma protein hyperphosphorylation and through activation of both cyclin D1͞cdk4 and cyclin E͞cdk2 kinases by a mechanism that depends on induction of cyclin D1 and cyclin E protein levels. The induction of cyclin D1 expression, but not that of cyclin E, is under mitogen-activated protein kinase (MAPK) control, indicating an independent regulation of these two cyclins in the 5-HT2B receptor mitogenesis. Moreover, by using the specific platelet-derived growth factor receptor (PDGFR) inhibitor AG 1296 or by overexpressing a kinasemutant PDGFR, we show that PDGFR kinase activity is essential for 5-HT2B-triggered MAPK͞cyclin D1, but not cyclin E, signaling pathways. 5-HT2B receptor activation also increases activity of the cyclins D1 and E ͉ G protein-coupled receptors ͉ platelet-derived growth factor receptor ͉ receptor signaling ͉ c-Src S erotonin (5-hydroxytryptamine, 5-HT) is involved in regulating cellular functions of central and peripheral nervous systems, endocrine and exocrine organs, as well as vascular and hematopoietic systems (1). These actions are mediated by numerous cognate receptors. For instance, 5-HT acts as a growth factor in a variety of cells, a function that is mediated by 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, or 5-HT2C receptor subtypes (2-5). The 5-HT2B receptor belongs to the G protein-coupled receptor (GPCR) family. Binding of 5-HT to 5-HT2B receptor activates G q protein, thereby stimulating phospholipase C, which initiates a rapid release of inositol trisphosphate and results in a rise in intracellular calcium levels (6). The signal transduction pathways activated downstream of the 5-HT2B receptor include the Ras and mitogen-activated protein kinase (MA PK of the MAPK͞ERK subfamily) pathways (3). Despite numerous studies of 5-HT signal transduction pathways, the critical steps from signal integration to its proliferative action have not been elucidated.The regulation of cell proliferation is a complex process controlled by external mitogenic factors. Once cells are induced to proliferate, passage through the mitotic cell cycle is directed by activation of a series of cyclins and their catalytic subunits, cyclin-dependent kinases (cdks) (7). Mitogenic factors act by stimulating both the proliferation of quiescent cells arrested in G 0 and the progression of the cell cycle through the restriction point in late G 1 . Progression through G 1 and the G 1 ͞S transition in mammalian cells is regulated by cdk4 and cdk6, which form complexes with cyclin D1, and by cdk2, which forms a complex with cyclin E (7). The G 1 cyclin͞cdk complexes drive the phosphorylation of retinoblastoma protein (pRb) that represents the limiting event in G 1 progression (8). However, the mechanism whereby 5-HT triggers G 1 progression has not been examined.The link between upstream signaling circuitry and the cellcycle machinery is of interest. Identified candid...

Mutation of 5-HT(2B) receptor leads to a cardiomyopathy without hypertrophy and a disruption of intercalated disks. 5-HT(2B) receptor is required for cytoskeleton assembly to membrane structures by its regulation of N-cadherin expression. These results constitute, for the first time, strong genetic evidence that serotonin, via the 5-HT(2B) receptor, regulates cardiac structure and function.