András Simon

The goal of this project is to reveal mechanisms underlying major cell state transitions and to understand how these mechanisms relate to vertebrate regeneration. We will primarily study newts, which are semi-aquatic salamanders, and which can regenerate complex structures, such as entire limbs. Limb regeneration depends on formation of a blastema which is derived from local, stably quiescent differentiated cells that re-enter the cell cycle and de-differentiate after an injury. These cell state transitions are reversible since de-differentiated cells readily re-differentiate, and most cell types regain exclusively their original tissue identity during the development of the blastema into a new limb. How such temporal suspension of cell identity is regulated at the molecular level is in the focus of the proposed work. Using molecular profiling and functional perturbation studies, together with extensive lineage tracing experiments, we aim: (1) to highlight small RNA regulated processes, and (2) to identify cellular sources responsible for the lifelong and seemingly unlimited regeneration potential of the newt limb after repeated injury/regeneration cycles. We expect the results not only to generate novel principles of cell fate determination but, based on cross-species analyses, also to render an explanatory framework for the uneven distribution of regenerative capacities among vertebrates.