5-HT2B receptor-mediated serotonin morphogenetic functions in mouse cranial neural crest and myocardiac cells

Abstract

During embryogenesis, serotonin has been reported to be involved in craniofacial and cardiovascular morphogenesis. The detailed molecular mechanisms underlying these functions, however remain unknown. From mouse and human species, we have recently reported the cloning of 5-HT2B receptors which share signal transduction pathways with other 5-HT2 receptor subtypes (5-HT2A and 5-HT2C). In addition to phospholipase C stimulation, it appears that these three subtypes of receptor transduce a common serotonin-induced mitogenic activity, which could be important for cell differentiation and proliferation. We have first investigated the expression of 5-HT2 receptor mRNAs in the mouse embryo. Interestingly, a peak of 5-HT2B receptor mRNA expression was detected 8–9 days postcoitum, whereas there was only low level 5-HT2A and no 5-HT2C receptor mRNA expression at this stage. Expression of this receptor was confirmed by binding assays using a 5-HT2-specific ligand which revealed a peak of binding to membrane preparations from 9 days postcoitum embryos. In addition, whole mount in situ hybridisation and immunohistochemistry on similar stage embryos detected 5-HT2B expression in neural crest cells, heart myocardium and somites. The requirement for functional 5-HT2B receptors between 8 and 9 days postcoitum is supported by culture of embryos exposed to 5-HT2-specific ligands; 5-HT2B high-affinity antagonist such as ritanserin, induced morphological defects in the cephalic region, heart and neural tube. These antagonistic treatments interfere with cranial neural crest cell migration, induce their apoptosis, and are responsible for abnormal sarcomeric organisation of the subepicardial layer and for the absence of the trabecular cell layer in the ventricular myocardium. This report indicates for the first time that 5-HT2B receptors are actively mediating the action of serotonin on embryonic morphogenesis, probably by preventing the differentiation of cranial neural crest cells and myocardial precursor cells.

Overexpression of 5-HT2B receptor results in retinal dysplasia and defective ocular morphogenesis in Xenopus embryos

“…Mouse embryos treated with 5-HT2 receptor antagonist (ritanserin) or genetically manipulated for the targeted inactivation of the 5-HT2B gene, display embryonic and neonatal death caused by heart defects. These studies, also supported by in vitro analyses, demonstrated that 5-HT via 5-HT2B receptor is an important regulator of cardiac myocytes differentiation, proliferation and survival (Yavarone et al, 1993, Choi et al, 1997Nebigil et al, 2000aNebigil et al, , 2003.…”

“…Although the exact developmental roles played by 5-HT have to be specified yet, evidence has been presented for its involvement in cell division and morphogenetic cell movements during cleavage and gastrulation, in the establishment of left-right asymmetry (Levin et al, 2006), in the closure of neural tube, and as differentiation signal for target neurons during early neurogenesis (Whitaker-Azmitia, 2001). In the mouse embryo 5-HT derived from maternalembryonic circulation regulates proliferation, migration, gene expression and morphogenesis of neural crest derived cell populations (Choi et al, 1997;Moiseiwitsch, 2000;Buznikov et al, 2001).…”

Serotonin Receptors

“…Arguably, the most important function of this receptor is during development, where it coordinates the proper formation of key structures such as the heart and brain. ,, In developing cardiomyocytes, serotonin, through 5-HT 2B receptors, signals through Gα q , phospoinositide 3-kinase (PI3K)/AKT, and ERK 1/2 pathways and activates NF-κB to regulate the mitochondrial adenine nucleotide translocator and cell survival and proliferation. , One of the more infamous roles of the 5-HT 2B receptor lies in its function in the adult heart, where its activation can lead to myofibroblast proliferation and valvular heart disease, as was the likely mechanism leading to the sometimes fatal pathologies observed in the hearts of patients taking the appetite suppressant combination “fen-phen”. , Both fenfluramine and its active metabolite norfenfluramine are 5-HT 2B receptor agonists . Whereas agonists of this receptor can produce valvulopathies and other cardiopulmonary problems, antagonists of this receptor may prove useful for treating diseases such as cardiac hypertrophy …”

Effect of Maternal Antidepressant Use During the Pre-pregnancy/Early Pregnancy Period on Congenital Heart Disease: A Prospective Cohort Study in Central China

“…Serotonin (5-HT) is a neurotransmitter that plays an important role in embryonic development as a signaling molecule (34). It is also reported that 5-HT may be involved in cardiac development, such as progenitor cell formation and outflow tract lengthening (35)(36)(37). SSRIs can cross the placental barrier and block 5-HT reuptake, which provides biological justification for their teratogenic effect on heart development (38).…”