THE ROLE OF THE P53/P66SHC PATHWAY IN DEVELOPMENT AND AGING: DANIO RERIO (ZEBRAFISH) AND NOTHOBRANCHIUS AS MODEL ORGANISMS

The transcriptional response to oxidative stress (OS) is involved in aging. As ROS-induced damages accumulate, cell senescence or apoptosis are triggered: these two mechanisms are implicated in the progressive physiological decay of the organism. Surprisingly, transcriptional pathways involved in OS-response play a role also in the balance between proliferation and differentiation during embryonic development. Recently, it has been discovered a transcriptional network that triggers cell cycle arrest in vitro upon OS. This pathway involves two well-known aging-associated genes: p53, with its short isoform Δ40p53, and p66Shc. Here we propose the use of two complementary model organisms, Danio rerio (zebrafish) and Nothobranchius furzeri, to unravel the p53/p66Shc pathway in vivo. We report here that Δ40p53 and p66Shc are conserved in these species, partially recapitulating mammalian functions. Moreover, our findings about the spatial and temporal regulation of p66Shc expression during zebrafish embryogenesis suggest that p66Shc has a role in neural development. Furthermore, we generated the first genetic model of Δ40p53 ablation in zebrafish, exploiting the CRISPR/Cas9 technology. The structure of the p53 locus in mouse does not allow to selectively knock-out Δ40p53 without depleting also p53 activity. Our Δ40p53-/- zebrafish model shows the unique opportunity to characterize the biological functions of Δ40p53 isoform in physiological development in a context where p53 expression is maintained unaltered. Finally, we provide preliminary data showing that Δ40p53 modulates in vivo p53-dependent transcriptional response to stress.