Brigitte Galliot (University of Geneva)
Hydra, a model for regeneration and slow aging
Department of Genetics and Evolution, University of Geneva, Switzerland.
(Host: Simona Chera)
In 1744, Abraham Trembley published his amazing discovery about the regeneration of a complete animal, the small freshwater cnidarian polyp named Hydra. But how does this animal trigger regeneration? After 110 years of work that include an extensive series of transplantation experiments (Browne, 1909; Shimizu, 2012), the production of a predictive models (Meinhardt and Gierer, 1972), and the dissection of cellular and molecular signaling, we know that the head only regenerates if a head organizer gets rapidly re-established in the regenerating tip (Bode, 2012; Vogg et al. 2016). This head organizer is made of two antagonistic components, the head activator that was characterized as Wnt/b-catenin signalling (Hobmayer et al., 2000; Lengfeld et al. 2009) and the head inhibitor that prevents ectopic head formation in intact and regenerative conditions.
We recently discovered that the transcription factor Sp5 acts as a head inhibitor (Vogg et al., 2019): Sp5expression is controlled by Wnt/b-catenin signaling, highest in the head and re-expressed during regeneration; Sp5 inhibits Wnt/b-catenin signaling by repressing Wnt3expression and knocking-down Sp5through RNAi triggers multiple head formation in intact and regenerating animals. When expressed in human cells, both Hydraand zebrafish Sp5do repress the activity of the Wnt3 promoter. Thus, we identified Sp5 as a repressor of Wnt/b-catenin signalling, a function conserved across eumetazoan evolution with a major developmental role in Hydra.
Hydrapossesses three active stem cell populations that continuously self-renew and prevent animal senescence. We identified two H. oligactis strains, one that rapidly develops an aging phenotype when undergoing gametogenesis upon cold exposure, and another strain resists to aging, therefore named Ho_CS (Cold Sensitive) and Ho_CR (Cold Resistant) respectively (Tomczyk et al., 2015). The epithelial stem cells exhibit strikingly different behaviors in these two strains: irreversibly reducing their self-renewal during aging in Ho_CSwhile remaining proliferative in Ho_CR. Also Ho_CSepithelial cells are deficient for autophagy when compared to Ho_CRor H. vulgarisones. Epithelial cells form less autophagosomes upon autophagy induction, and accumulate the autophagy cargo receptor p62/SQSTM1, a sign of autophagy blockade. This poorly inducible autophagy flux, also observed in asexual Ho_CSanimals, is confirmed by the in vivoimaging of epidermal epithelial cells expressing the mCherry-eGFP-LC3A/B dual autophagy sensor. In low-senescent H. vulgarisanimals, the autophagy flux is efficient and easily inducible, and knocking-down WIPI2, which is critical for autophagosome formation, blocks autophagy and induces aging. This study highlights the essential role of a dynamic autophagy flux on epithelial stem cell renewal to maintain low senescence,a longevity mechanism that values Hydrafor aging studies (Tomczyk et al. BioRXiv 2017).