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Notch signalling in Hydra head regeneration

Hydra is one of the most basal animals and a classical model of regeneration. These polyps display an amazing plasticity as they can regenerate a whole animal from a tiny piece of their bodies, can reproduce asexually by budding and, amazingly, dissociated cells can re-aggregate to form a new individual. Hydra has a well-established oral-aboral axis. In the head (oral) region there is a hypostome and a ring of tentacles. Many studies have reported that the tip of the head has an organizing activity. Thus, if this head tip is transplanted into the body column it is able to induce a new head and a secondary axis. This organizing activity appears to be controlled by the Wnt/Beta-catenin pathway. HyWnt3 is expressed at the tip of the head in intact and regenerating animals. Ectopic induction of Wnt signalling in the body column induces secondary axes all along it.

In a recent paper from the laboratory of Angelika Böttger the authors describe how Notch signalling plays a key role in maintaining and re-establishing the Hydra head (http://www.ncbi.nlm.nih.gov/pubmed/24012879). Notch signalling is a well-known and highly conserved pathway that plays a role, among other, in establishing well-defined boundaries as it can specify different cell fates in two adjacent cells. Once Notch transmembrane receptor is bound by a ligand the intracellular domain of the Notch receptor (NICD) is, then, cleaved and can go to the nucleus where it works as a co-activator of target genes. DAPT is a well-known inhibitor of the Notch pathway as it prevents cleavage of the active NICD and it is usually used in different animal models.

Upon culturing intact Hydras in DAPT for 48h the authors saw how the tentacles were shortened (beginning after 24h of treatment). After 48h of treatment DAPT was removed and in the following days these polyps displayed different levels of abnormalities in the patterning of their tentacles and heads, and even a new secondary hypostome appeared in some of them.  At the molecular level, the expression pattern of HyWnt3 at the tip of the hypostome was not affected by DAPT treatment. However, the expression of HyAlx (a marker or tentacle boundary) was severely affected. Previous studies had suggested that HyAlx might play a role in the specification of tissue for the formation of the tentacles. The results presented here support this view and point out Notch signalling as required for proper HyAlx expression and, therefore, differentiation of tentacles.

Next, the authors analysed the function of Notch signalling during head regeneration. In most of their experiments the animals were treated with DAPT for 24h prior to amputation. After 24h of regeneration in DAPT, this inhibitor was then removed from the medium and the animals were analyzed at different time points of further regeneration. After 60h only 18% of the animals had regenerated their heads. This lack of head regeneration can be explained because of the lack of re-establishment of a new head organizer. Thus, whereas in controls HyWnt3 is initially expressed in the regenerating tip in a broad cap-like pattern and then it becomes restricted to the tip of the new hypostome (around 36hpa), DAPT prevented the expression of HyWnt3 for up to 48h of regeneration. A similar result was observed for HyB-catenin. To check that DAPT really inhibits the formation of a head organizer the authors transplanted 24h regenerating tips of DAPT treated animals into the body column of host polyps. Only in 25% of the transplants a secondary axis developed in sharp contrast to the 100% of secondary axes observed when transplanting the regenerating tips of control animals.

Finally, the authors checked the expression of HyAlx during regeneration. In controls HyAlx is initially expressed in the whole regenerating tip (at 24h). At 48h this gene gets restricted to 4 or 5 rings at the sites where the tentacles will emerge. In DAPT-treated polyps, the initial expression of HyAlx appears normal but it never gets confined to 4 or 5 rings and it remains in the whole regenerating tip and gets expanded, suggesting that the whole tip had characteristics of tentacle precursors. Finally, the authors checked that upon DAPT treatment the expression of HyNotch in the regenerating tip is not affected but that of HyHes, a target of Notch signalling is abrogated.

Whereas in intact Hydra the authors suggest that Notch signalling is required to define the tentacle boundary, during regeneration Notch would be required to separate tentacle and hypostome cell fate. In their model, the Notch signal-receiving cells suppress the tentacle fate and become hypostomal cells by stabilizing the expression of HyWnt3 and HyB-catenin. Consequently, the inhibition of Notch signalling would allow the observed increased in tentacle cell fate and the lack of the Wnt/beta-catenin-mediated re-establishment of the head organizer.

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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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