Abstract
BackgroundSerotonin is a phylogenetically ancient molecule that is widely distributed in most metazoans, including flatworms. In addition to its role as a neurotransmitter, serotonin acts as a morphogen and regulates developmental processes. Although several studies have focused on the serotonergic nervous system in parasitic flatworms, little is known on the role of serotonin in flatworm development.MethodsTo study the effects of serotonin on proliferation and development of the cestode Echinococcus multilocularis, we cloned the genes encoding the E. multilocularis serotonin transporter (SERT) and tryptophan hydroxylase (TPH), analyzed gene expression by transcriptome analysis and whole mount in situ hybridization (WMISH) and performed cell culture experiments.ResultsWe first characterized orthologues encoding the SERT and TPH, the rate-limiting enzyme in serotonin biosynthesis. WMISH and transcriptomic analyses indicated that the genes for both SERT and TPH are expressed in the parasite nervous system. Long-term treatment of parasite stem cell cultures with serotonin stimulated development towards the parasite metacestode stage. Mature metacestode vesicles treated with serotonin showed increased rates of incorporation of the thymidine analogue 5-ethynyl-2′-deoxyuridine (EdU), indicating stimulated cell proliferation. In contrast, treatment with the selective serotonin reuptake inhibitor paroxetine strongly affected the viability of parasite cells. Paroxetine also caused structural damage in metacestode vesicles, suggesting that serotonin transport is crucial for the integrity of parasite vesicles.ConclusionsOur results indicate that serotonin plays an important role in E. multilocularis development and proliferation, providing evidence that the E. multilocularis SERT and TPH are expressed in the nervous system of the protoscolex. Our results further suggest that the E. multilocularis SERT has a secondary role outside the nervous system that is essential for parasite integrity and survival. Since serotonin stimulated E. multilocularis metacestode development and proliferation, serotonin might also contribute to the formation and growth of the parasite in the liver.Graphical
Highlights
Serotonin is a phylogenetically ancient molecule that is widely distributed in most metazoans, including flatworms
The E. multilocularis serotonin transporter and tryptophan hydroxylase show high homologies to their human homologues within the active domains Previous in silico analyses showed that a canonical serotonergic pathway, with exception of the monoamine oxidase and serotonin receptor 3, is encoded in both the E. granulosus and E. multilocularis genomes
Domain analysis with SMART 8.0 showed that E. multilocularis serotonin transporter (SERT) contained a Sodium neurotransmitter symporter family (SNF) domain (PF00209) with 12 transmembrane domains, demonstrating the typical domain structure of a neurotransmitter transporter with sodium symporter activity
Summary
Serotonin is a phylogenetically ancient molecule that is widely distributed in most metazoans, including flatworms. In addition to its role as a neurotransmitter, serotonin acts as a morphogen and regulates developmental processes. Several studies have focused on the serotonergic nervous system in parasitic flatworms, little is known on the role of serotonin in flatworm development. In addition to its role as a neurotransmitter, serotonin is known to act as a morphogenic factor that influences developmental processes [19]. In a previous study we and our colleagues showed that exogenously supplied serotonin induces re-differentiation of E. granulosus protoscoleces towards the metacestode stage [4]. Whether this is the case for E. multilocularis has not been investigated to date. The influence of serotonin on other larval transitions, such as the development of the oncosphere towards the metacestode or the proliferation of metacestode vesicles, has not yet been addressed
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