Thesis defense: « Deciphering the molecular dynamic underlying the initiatoin of whole body regeneration in the sea anemone Nematostella vectensis » – Rita ANDREONI

Amphithéâtre du CAL

Thesis directors : Aldine AMIEL & Eric RÖTTINGER

Abstract : Regeneration is a biological process that enables organisms to replace lost or damaged tissues, organs, or entire body parts. While regeneration shares common cellular and molecular mechanisms across species, its extent and efficiency vary widely. In the context of my PhD, I investigated the remarkable capacity of whole-body regeneration (WBR) of the sea anemone Nematostella vectensis. 

This thesis was structured around two main axes:

The first axis addressed a long-standing question in the field, wondering to what extent regeneration redeploys embryonic gene regulatory networks (GRNs)? To investigate this, we compared the GRN underlying embryogenesis to the one of whole-body regeneration in Nematostella vectensis. We found that regeneration re-uses components of the embryonic GRN, particularly the canonical Wnt (cWnt) and MEK/ERK pathways, along with a distinct set of regeneration-specific genes, including those associated with apoptosis. Perturbation of all three pathways highlighted that they are required for regeneration but at different steps. While cWnt and apoptosis are specifically required for the onset of cell proliferation, MEK/ERK signaling is essential earlier, not only for the cell proliferation but most importantly to initiate a tissue contact (TC) between the mesenteries (MES) and the body wall epithelia (BWE) at the amputation site. Globally, this work highlights that embryonic GRN modules are redeployed during regeneration but in a rewired manner and interconnected with regeneration-specific elements. 

The second axis focused on the tissue dynamics, molecular basis of TC, and molecular exchanges between MES and BWE for successful TC and regeneration initiation in Nematostella vectensis. A previous study showed that TC is a proliferation-independent mechanism, fundamental to regeneration. In this thesis, by combining morphological, cellular, and molecular analyses, we showed that the TC is accompanied by the fusion of retractor (located in the MES) and parietal (located in the BWE) muscles, between 12 and 14 hours post-amputation. Differential transcriptomic RNAseq tissue-specific analysis between MES and BWE during regeneration revealed: i) a strong molecular specific identity for each of these two entities, and ii) limited modulation of signaling pathways and cellular processes prior to the TC, while a higher diversity was observed after the initiation of the TC. Interestingly, we found that the FGF pathway and muscle contraction were specifically up- and down-regulated prior to TC, respectively. Inhibition of the FGF pathway blocks regeneration by preventing TC, cell proliferation and stem cell migration. Molecular analyses focusing on the role of the FGFR/MEK/ERK pathway identified a core set of 84 genes potentially critical for triggering TC and enabling successful regeneration.

Overall, this research underscores both the conservation and plasticity of gene regulatory networks associated with different developmental trajectories leading to the same outcome, i.e. a functional whole body. It also highlights the importance of inter-tissue communication as a key checkpoint to initiate and coordinate the cellular and molecular mechanisms that drive successful whole-body regeneration. Using an emerging non-conventional research model, these findings offer new insights into the mechanisms underlying the molecular, biological and tissular processes underlying WBR. These are valuable for future comparative studies and provide a deeper understanding of the diversity of metazoan regenerative capacities.