Abstract
Warm-blooded vertebrates regenerate lost limbs and their parts in general much worse than fishes and amphibians. We previously hypothesized that this reduction in regenerative capability could be explained in part by the loss of some genes important for the regeneration in ancestors of warm-blooded vertebrates. One of such genes could be ag1, which encodes secreted protein disulfide isomerase of the Agr family. Ag1 is activated during limb and tail regeneration in the frog Xenopus laevis tadpoles and is absent in warm-blooded animals. The essential role of another agr family gene, agr2, in limb regeneration was demonstrated previously in newts. However, agr2, as well as the third member of agr family, agr3, are present in all vertebrates. Therefore, it is important to verify if the activity of ag1 lost by warm-blooded vertebrates is also essential for regeneration in amphibians, which could be a further argument in favor of our hypothesis. Here, we show that in the Xenopus laevis tadpoles in which the expression of ag1 or agr2 was artificially suppressed, regeneration of amputated tail tips was also significantly reduced. Importantly, overexpression of any of these agrs or treatment of tadpoles with any of their recombinant proteins resulted in the restoration of tail regeneration in the refractory period when these processes are severely inhibited in normal development. These findings demonstrate the critical roles of ag1 and agr2 in regeneration in frogs and present indirect evidence that the loss of ag1 in evolution could be one of the prerequisites for the reduction of regenerative ability in warm-blooded vertebrates.
Highlights
Proteins of the anterior gradient (Agr) family belong to the superfamily of protein disulfide isomerases (PDI), all members of which contain the thioredoxin motif and are localized in the endoplasmic reticulum (ER) where they participate in the folding of various proteins (Park et al, 2009; Delom et al, 2020)
Using the regeneration of the amputated tails as a model, we decided to verify if such activation of the expression of these two genes is necessary for successful tail regeneration
We arranged a series of experiments in which we investigated the effects on tail regeneration of the downregulation of ag1 and agr2, alone or together, provoked by the antisense morpholino oligonucleotides (MO) to their mRNA
Summary
Proteins of the anterior gradient (Agr) family belong to the superfamily of protein disulfide isomerases (PDI), all members of which contain the thioredoxin motif and are localized in the endoplasmic reticulum (ER) where they participate in the folding of various proteins (Park et al, 2009; Delom et al, 2020). Despite the role of agr in newt limb regeneration being established (Kumar et al, 2007; Grassme et al, 2016) and elevated expression of ag and agr being shown during the regeneration of the frog (Xenopus laevis) tadpoles limbs and tails (Ivanova et al, 2013), it is still unknown whether these two genes play critical roles in frogs’ regeneration abilities. We found that both overexpression of either of these two genes and treatment of tadpoles with the recombinant protein product of either of them restores regeneration in the refractory period when amputated tail tips cannot regenerate in normal development (Slack et al, 2004) These results confirm the critical role of ag and agr for regeneration in frogs and provide an additional argument in favor of the hypothesis that connects reduction of the regenerative abilities in warm-blooded vertebrates with the loss of some important genes, in particular ag, in their ancestors
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