BMB Section Seminar: "A potential role for serotonin in regulating human ES cells and blastocysts"
Dr. Athina Samara, J. Glover lab, Institutt for medisinske basalfag, UiO
Confocal image of human stem cells. Photo: Athina Samara
Serotonin (5-hydroxytryptamine, 5HT) is a major neuromodulatory neurotransmitter and hormone in nearly all animal species. The effects of serotonin are exerted via 7 subtypes of 5HT receptors (5HTRs) , of which 6 are G-protein-coupled receptors (5HTR1, 2, 4, 5, 6, and 7) and one is a ligand-gated ion channel (5HTR3) . The physiological effects of serotonin include regulation of subcortical sensory and motor systems and of higher cognitive functions, and dysregulation of serotonin is implicated in a myriad of neuropathologies, including pain syndromes, motor, sleep, eating and mood disorders. During mammalian development, 5HT has been implicated in regulating neurodevelopmental processes, and alterations of the fetal 5HT supply can have adverse effects on neural circuit formation . 5HT has been detected in embryos or larvae of rodent and non-mammalian species, where it is believed to have important signaling functions.
Nothing is known, however, about the effects of 5HT in preimplantation human embryos. To address this question, we have assessed the expression of 5HTRs in day 5 human blastocysts and in 16 hES cell lines. Four hESC lines were then tested for 5HTR-mediated changes in cell proliferation, signaling, gene and protein expression after exposure to 5HT.
We detected transcripts of most 5HTR subtypes in blastocysts, and of all 5HTR subtypes in every hES cell line. In hES cells, 5HT exposure upregulated transcription of all 5HTRs, and of selected stemness, proneural and serotonergic specification and pathway genes. Cell cycle entry was accelerated 3h after 5HT exposure, and transcription of cyclins D1-3 and of Cdk4 and 6 was upregulated 3h after cell arrest release in the presence of 5HT. Phosphorylation of STAT3, ERK1/2 and AKT was significantly increased by exposure to 5HT within 5 minutes.
These results indicate that the activation of 5HTRs stimulates hES cells towards increased proliferation and regulates the expression of a broad spectrum of stemness and differentiation genes. Current experiments are focused on dissecting the effects of specific 5HTRs.
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