Reactivation and reprogramming of spinal progenitors into a unique neuro-regenerative state

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After a spinal cord injury, nerve connections are severed and nerve cells near the injury die, leading to permanent disabilities. In mammals, stem cells in the spinal cord fail to replace lost nerve cells. However, in zebrafish these stem cells generate new nerve cells after injury that aid the repair process. Thus, the zebrafish model offers an opportunity to elucidate the necessary steps for successful regeneration. We have previously shown that spinal stem cells activate mechanisms that are unique to the regeneration process and not a mere recapitulation of development. Here, we propose a genomics project in which we compare gene regulation and gene activity in injured spinal stem cells at different developmental stages and after manipulations of repair processes in zebrafish. In this way we can computationally tease out crucial cellular programmes that are related to reactivation from a dormant state and reprograming of spinal stem cells to replace lost nerve cells. Finally, we will confirm the functional importance of pivotal genes and their regulatory elements using CRISPR/Cas9 technology. Thus we hope to make fundamentally important observations on gene-regulatory programmes that are specific to successful regeneration. At the same time, the identified molecular steps in achieving replacement of lost nerve cells will serve as a blueprint for therapeutic efforts in mammals to overcome the inefficient reprogramming of stem cells to successful replacement of nerve cells there.