Abstract
Sphingosine-1-phosphate is a bioactive lipid and a signaling molecule integrated into many physiological systems such as differentiation, proliferation and migration. In mammals S1P acts through binding to a family of five trans-membrane, G-protein coupled receptors (S1PRs) whose complex role has not been completely elucidated. In this study we use zebrafish, in which seven s1prs have been identified, to investigate the role of s1pr1. In mammals S1PR1 is the most highly expressed S1P receptor in the developing heart and regulates vascular development, but in zebrafish the data concerning its role are contradictory. Here we show that overexpression of zebrafish s1pr1 affects both vascular and cardiac development. Moreover we demonstrate that s1pr1 expression is strongly repressed by miR-19a during the early phases of zebrafish development. In line with this observation and with a recent study showing that miR-19a is downregulated in a zebrafish Holt-Oram model, we now demonstrate that s1pr1 is upregulated in heartstring hearts. Next we investigated whether defects induced by s1pr1 upregulation might contribute to the morphological alterations caused by Tbx5 depletion. We show that downregulation of s1pr1 is able to partially rescue cardiac and fin defects induced by Tbx5 depletion. Taken together, these data support a role for s1pr1 in zebrafish cardiovascular development, suggest the involvement of this receptor in the Tbx5 regulatory circuitry, and further support the crucial role of microRNAs in early phase of zebrafish development.
Highlights
Sphingosine-1-phosphate (S1P) is a biologically active lysophospholipid with crucial role for membrane structure and function in eukaryotes
We have recently shown that Tbx5 depleted zebrafish embryos show a decreased level of miR-19a, and we demonstrated that miR-19a replacement partially rescues fin and cardiac defects caused by Tbx5 depletion (Chiavacci et al, 2015)
In this study we have uncovered a role of s1pr1 in zebrafish cardiac development
Summary
Sphingosine-1-phosphate (S1P) is a biologically active lysophospholipid with crucial role for membrane structure and function in eukaryotes. Data concerning the s1pr function in zebrafish are rather controversial: several papers in recent years highlighted the s1pr role in vascular development and in controlling the venous endothelial barrier integrity, similar to the role played by this receptor in mouse (Ben Shoham et al, 2012; Gaengel et al, 2012; Tobia et al, 2012; Mendelson et al, 2013). They demonstrated that none of the s1pr mutants showed developmental defects with the exception of s1pr mutant which exhibits embryonic lethality arising from its cardiac defect (Hisano et al, 2015) These data suggest a previously unrevealed redundancy in functions of the S1P receptor-mediated signaling in zebrafish to the partially overlapping expression of S1P receptors observed in mouse (Means and Brown, 2009). We show that s1pr during the early zebrafish developmental stages is controlled by miR-19a and as such might be part of the Tbx5/miR-19a regulatory circuit affecting heart development
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