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ChroNeuroRepair Report Summary

Project ID: 340793
Funded under: FP7-IDEAS-ERC
Country: Germany

Periodic Report Summary 2 - CHRONEUROREPAIR (Chromatin states in neurogenesis – from understanding chromatin loops to eliciting neurogenesis for repair)

Here we study in Aim 1 the mechanisms of neurogenesis when they work best, namely during brain development, in order to implement them in Aim 2 for neuronal repair after brain injury by pursuing a highly innovative approach which we pioneered already in 2002, namely to convert reactive glial cells into neurons. In Aim 1 we have made great progress in regard to identifying novel mechanisms of neurogenesis by identifying novel interactors of Trnp1, a key regulator of neural stem cells and brain folding. Moreover, we showed that the virtual absence of DNA-methylation in cerebral cortex development has little effect on proliferation, neurogenesis and cell fate decisions (Ramesh, Bayam et al., Genes and Development 2016). However, a small subset of endogenous retroviral elements was de-repressed by a novel, Tet-mediated mechanism involving Uhrf1 (Ramesh, Bayam et al., 2016). This eventually lead to cause neurodegeneration. In Aim2 we made major progress by identifying that the molecular mechanisms of converting the same glial cell type into GABAergic or glutamatergic neurons are rather different (Masserdotti, Gillotin et al., Cell Stem Cell 2015) with the exception of a few pan-neuronal regulators including Trnp1. To monitor the conversion in vivo after brain injury we started by determining the transcriptome of reactive astrocytes (Sirko et al., Glia 2015) to identify further factors promoting reprogramming. A breakthrough discovery was the identification of ferroptosis due to excessive reactive oxygen species as a major hurdle in direct neuronal reprogramming when cells with largely glycolytic metabolism are converted into neurons that largely use a different metabolism based on oxidative phyosphorylation (Gascón, Murenu et al., Cell Stem Cell 2016). Protection from cell death and excessive reactive oxygen species allows reprogramming efficiencies of more than 90% in the stab wound injured murine brain in vivo. Last, but not least we could also answer a long-standing question for neuronal repair, namely to which extent new neurons can integrate into an adult brain region that normally never incorporates new neurons. Excitingly, we could show that this is indeed possible with high accuracy as transplanted neurons integrated with exquisite specificity into the injured murine cerebral cortex receiving brain-wide only adequate input and achieving their adequate functional receptive field properties (Falkner, Grade et al., Nature 2016).

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