Abstract
The chemokine stromal cell-derived factor-1 (SDF1) was originally identified as a pre-B cell stimulatory factor but has been recently implicated in several other key steps in differentiation and morphogenesis. In addition, SDF1 as well as FGF signalling pathways have recently been shown to be involved in the control of epimorphic regeneration. In this report, we address the question of a possible interaction between the two signalling pathways during adult fin regeneration in zebrafish. Using a combination of pharmaceutical and genetic tools, we show that during epimorphic regeneration, expression of sdf1, as well as of its cognate receptors, cxcr4a, cxcr4b and cxcr7 are controlled by FGF signalling. We further show that, Sdf1a negatively regulates the expression of fgf20a. Together, these results lead us to propose that: 1) the function of Fgf in blastema formation is, at least in part, relayed by the chemokine Sdf1a, and that 2) Sdf1 exerts negative feedback on the Fgf pathway, which contributes to a transient expression of Fgf20a downstream genes at the beginning of regeneration. However this feedback control can be bypassed since the Sdf1 null mutants regenerate their fin, though slower. Very few mutants for the regeneration process were isolated so far, illustrating the difficulty in identifying genes that are indispensable for regeneration. This observation supports the idea that the regeneration process involves a delicate balance between multiple pathways.
Highlights
Epimorphic regeneration requires the mobilization, as well as the migration and the proliferation of progenitor cells capable of restoring the missing part
In order to investigate the possible regulation of Sdf1 and its receptors by the fibroblast growth factors (Fgfs) signalling pathway, activity of the fibroblast growth factor receptors (FgfRs) was blocked using the drug SU5402, a drug first described as a specific inhibitor for FgfR1 phosphorylation [31]
It should be noted that SU5402 blocks FgfR1 activity by binding to a region well conserved in all four FgfRs, and so it might act on several of these receptors [32]
Summary
Epimorphic regeneration requires the mobilization, as well as the migration and the proliferation of progenitor cells capable of restoring the missing part. This phenomenon presents an interesting opportunity for studying the coordination between proliferation and patterning, as both processes must be strictly regulated in time and space to ensure the restoration of the size and shape of the missing part. Upon FGF binding, the receptors homodimerize and are autophosphorylated, leading to the activation of the kinase activity. This triggers a cascade of intracellular signals ending in the activation of target genes in the nucleus. Even though the signal transduction mechanisms by which FGFs function have been well characterized [11], identification of the targets genes is still limited
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