Unraveling new roles for serotonin receptor 2B in development: key findings from Xenopus

Abstract

The serotonin receptor 5-HT2B has been shown to be critically important during embryogenesis as the knockout of this gene in mice causes heart defects and embryonic lethality that impairs further analyses on other embryonic cell and tissue types. In the present review, we highlight how the use of Xenopus laevis, an alternative vertebrate model suitable for gene loss and gain of function analyses, has contributed to our understanding of the role of 5-HT2B signaling during development. In vivo studies showed that 5-HT2B signaling is not only required for heart development, but that it also has a crucial role in ocular and craniofacial morphogenesis, being involved in shaping the first branchial arch and the jaw joint, in retinogenesis and possibly in periocular mesenchyme development. These findings may be relevant for our understanding of congenital defects including human birth malformations. In addition, 5-HT2B appears to be required for the therapeutic actions of selective serotonin reuptake inhibitors commonly prescribed as antidepressant drugs to pregnant and lactating women. We discuss how the understanding of the molecular basis of serotonin signaling in a suitable animal embryogenesis model may open new lines of investigations and therapies in humans. KEY WORDS: 5-HT2B, neural crest cell, eye, craniofacial morphogenesis, SSRISerotonin, an ancient molecule with unsuspected and still unveiled functions Serotonin (5-hydroxytryptamine, 5-HT) is a phylogenetically ancient monoamine that fulfills a broad role in the control of many vital functions including the control of gastrointestinal motility and secretion, cardiovascular regulation, hemostatic processes, the regulation of circadian rhythms, the control of the sleep-wake cycle, memory and learning, perception of pain, appetite and sexual behavior (reviewed by Berger et al., 2009). The broad action of the serotonin signaling system has attracted the interest of researchers in various fields of biology and molecular medicine, spanning from developmental biology, neurobiology to molecular psychiatry. 5-HT is best known for its role in the nervous system where it is one of the neurotransmitters mainly involved in the etiology of various human psychiatric disorders, including anxiety, depression, obsessive-compulsive disorders, schizophrenia, pain and migraine. Accordingly, many substances that interfere with the serotonergic system are commonly used as therapeutic agents. Selective serotonin reuptake inhibitors (SSRIs) are, in fact, the most frequently prescribed drugs for the treatment of depression Int. J. Dev. Biol. 57: 707-714 (2013) Abbreviations used in this paper: 5-HT, serotonin; 5-HTT, serotonin transporter; CNS, central nervous system; CMZ, ciliary marginal zone; Edn1, endothelin 1; GCL, gaglion cell layer; INL, inner nuclear layer; NCCs, neural crest cells; POM, periocular mesenchyme; SSRI, selective serotonin reuptake inhibitors; Tph2, tryptophan hydroxylase 2.and anxiety-related disorders (Berton and Nestler, 2006). These drugs inhibit...

Sex-dependent dominance maintains migration supergene in rainbow trout

“…A missense mutation within RX3 was predicted to have an effect on phenotype (polyphen2 analysis Thr279Ile, naïve Bayes posterior probability 0.846, sensitivity = 0.83, specificity = 0.93). Additionally, the serotonin receptor, 5-HT2B , a neurotransmitter with effects on both behaviour and retinal development 51,52 , contains two segregating missense mutations. The homeolog of the pericentromeric region on Omy12 has also been implicated in migratory phenotype 53,54 , supporting a role for these genes and that differences in both the phenotype and visual signalling can also be generated independently of the Omy05 rearrangement via parallel selection on gene duplicates.…”

The Risk of Congenital Heart Anomalies Following Prenatal Exposure to Serotonin Reuptake Inhibitors—Is Pharmacogenetics the Key?

“…Other polymorphisms, on the other hand, were shown to reduce the response of several SRIs, e.g., HTR1A rs6295 in the treatment of fluoxetine, fluvoxamine, and citalopram [138,139,140,141] Furthermore, an increase in side effects of paroxetine was reported among patients with HTR2A rs6313 , HTR3B rs1176744 and HTR3B rs3831455 [132,142,143]. Unlike other genes, there are limited data on the polymorphisms of the gene encoding for the 5-HT2B receptor, which is more important, in this regard, in the developmental stage of the foetal heart [118,119,144]. …”

Neurotransmitter signaling pathways required for normal development inXenopus laevisembryos: a pharmacological survey screen

“…; Ori et al. ; Pratt & Khakhalin, ; Schmitt et al. ), as well as for studies of developmental toxicology (Sunderman et al.…”

“…Information on involvement of neurotransmitters in pattern formation would not only identify novel components of embryogenesis, but also give important insight into potential new endpoints for teratogenic (embryotoxic) effects of widespread pharmaceuticals (Alwan et al 2007;Louik et al 2007;Colvin et al 2011;Myles et al 2013;Hurault-Delarue et al 2014;Yazdy et al 2014). To begin to identify possible patterning roles for other neurotransmitter families, this study took advantage of compounds developed for neuropharmacological research, and an exploratory drug screen was conducted in the Xenopus laevis embryo, a popular vertebrate model for the study of well-conserved developmental mechanisms (Kaltenbrun et al 2011;King et al 2012;Ori et al 2013;Pratt & Khakhalin, 2013;Schmitt et al 2014), as well as for studies of developmental toxicology (Sunderman et al 1991(Sunderman et al , 1992Fort et al 1992;Mouche et al 2011;Leconte & Mouche, 2013). This preliminary screen represents the first tier of an inverse drug screen, of the variety described by (Adams & Levin, 2006), in which drugs are tested in a hierarchical manner according to target specificity, to rapidly bypass large families with no apparent roles and progressively home in on targets with interesting functions.…”