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Attenuated RA signaling during Xenopus lens regeneration

Different vertebrate species such as newts, salamanders, fish and Xenopus are capable of regenerating their lenses. In newts and salamanders lens regeneration occurs through transdifferentiation of the pigmented iris epithelium. In newts transdifferentiation occurs from cells in the dorsal epithelium whereas in axolotls, both dorsal and ventral pigmented iris epithelium cells can regenerate the lens. On the other hand, in Xenopus, lenses are regenerated from the cornea. The factors that make the cornea competent for lens regeneration are not very well known yet. Recently, it has been suggested that in Xenopus, lens regeneration may occur not from cornea transdifferentiation but from a population of multipotent corneal stem cells (http://www.ncbi.nlm.nih.gov/pubmed/23274420). Now, a paper also from the laboratory of John Henry reports on the role of retinoic acid (RA) during Xenopus lens regeneration (http://www.ncbi.nlm.nih.gov/pubmed/24384390).

RA plays many important roles during the development and regeneration of a large variety of organs. In newts, RA signaling is required for proper lens regeneration. Here, the authors investigated the role of this signaling in Xenopus. They first analyzed the expression of aldh1a1, aldh1a2 and aldh1a3, required for the synthesis of endogenous RA. They also examined the expression of cyp26a1, cyp26b1 and cyp26c1. CYP26 is an enzyme of the cytochrome P450 family that regulates RA by metabolizing it. They found that all these 6 transcripts, except cyp26c1, were expressed in the cornea of control and regenerating tissues. To analyze the role of RA signaling in Xenopus lens regeneration they cultured lentectomized eyecups in the presence of different agonists and antagonists of this pathway. When they used Liarozole, an antagonist of CYP26, lens regeneration was strongly inhibited. These results suggested that CYP26 activity was required for regeneration pointing out the possibility that RA levels were needed to be reduced for a successful regeneration. This was further supported when they used TTNPB, an RA analog that is resistant to CYP26. Treatment with TTNPB also inhibited lens regeneration. Finally, the exogenous application of RA at a 20mm concentration also impaired lens regeneration (lower doses of exogenous RA did not affect regeneration).

Cyp26 genes are upregulated in response to RA. Therefore, to check whether Liarozole and TTNPB affected RA signaling they checked the expression of cyp26a1 in drug-treated tissues. In all cases the expression of cyp26a1 was strongly upregulated suggesting an activation of RA signaling after those treatments that would correlate with the inhibition of lens regeneration.

However, the application of exogenous RA at 1mm also induced cyp26a1 expression without inhibiting regeneration. Therefore, cyp26a1 over-expression can be seen as a readout of RA activity but by itself would not be the responsible of the inhibition of lens regeneration. Next, the authors used inhibitors of RA signaling and they observed how their application did not inhibit lens regeneration, further supporting the idea that RA signaling does not seem to be required for regeneration.

Finally, the authors checked that treatment with Liarozole reduced cell proliferation but TTNPB and exogenous RA did not have a significant impact on cell proliferation, suggesting that Liarozole effects on cell division may not result from increased RA levels. Also, the authors checked the expression of three putative corneal stem cell markers (sox2, oct60 and p63). What they saw was that Liarozole treatment, although inhibiting lens regeneration, did not affect the expression of these genes. On the other hand, exogenous RA at 1mm did not inhibit regeneration but altered the expression of these three genes. Therefore, the fact that RA activity appears to inhibit lens regeneration does not seem to be related to the expression of these genes.

In summary, although further studies are required to better understand the exact function of RA signaling on lens regeneration in Xenopus it seems clear that in contrast to what happens in newts, RA activity needs to be attenuated for a successful regeneration in these frogs.

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Francesc Cebrià

Francesc Cebrià

Francesc Cebrià

I am a Biologist and Professor at the University of Barcelona. I do my research on a fascinating animal: freshwater planarians. You can cut them in as many pieces as you want and each piece will regenerate a complete new flatworm in very few days. In this blog I will keep you updated on the latest news on the field of animal regeneration. You will be able to follow the latest research on how planarians, axolotls, newts, cnidarians and other animals are able to regenerate parts of their bodies

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