Final Report Summary - CHRONEUROREPAIR (Chromatin states in neurogenesis – from understanding chromatin loops to eliciting neurogenesis for repair)
Our work examines the mechanisms of neurogenesis with the final aim to utilize them for repair purpose. With the help of the ChroNeuroRepair advanced ERC grant we could make major steps forward in both areas – our understanding of mechanisms in the developing brain and using them to turn reactive glia into new neurons for repair., and make some seminal unexpected discoveries.
Towards basic understanding of neurogenesis in the developing brain we have identified novel molecular mechanisms regulating neural stem cell self-renewal and differentiation. In particular, the novel nuclear protein Trnp1 that regulates neural stem cell self-renewal and brain folding, is essential also for conversion of glial cells into neurons, independent of the specific transcription factor used in this conversion process (Masserdotti et al., 2015). We found that Trnp1 acts as a master regulator of nuclear membrane-less organelles by liquid-liquid-phase transition and further unraveled a novel player in regulating neuronal maturation and survival (Ramesh et al., 2016). These discoveries together with identification of novel hurdles in direct reprogramming of glia to neurons allowed us to hugely improve this highly innovative approach for neuronal replacement now achieving more than 90% efficiency in the injured murine brain in vivo (Gascon et al., 2016; Mattugini et al., 2019). Having moved direct reprogramming to such a promising outcome, we turned to another major question, namely to which extent new neurons can adequately integrate when transplanted into an injured brain region that normally does not integrate new neurons. We discovered that this works amazingly well with the new neurons receiving brain-wide only adequate input connectivity and developing their appropriate functional network properties (Falkner, Grade et al., 2016). This grant therefore helped to pave the way towards neuronal replacement therapy and unravel crucial basic mechanisms of neurogenesis.
As research is never fully directed but also often yields surprises, we identified a novel centrosome protein, Akna, that was previously considered a transcription factor and we thought would be a counteracting Trnp1 function. It does indeed counteract Trnp1 function by mediating neural stem cells to leave the stem cell niche and differentiate, but it does so by orchestrating microtubules at the centrosome and thereby weaking junctional coupling to neighboring neural stem cells (Camargo et al., 2019). Most importantly, this mechanism applies not only in the nervous system, but also for other cells leaving an epithelium and may hence pave the way to novel approaches interfering with metastasis formation. These results thus show how investing into basic research leads to pioneering discovery of novel treatment options.
Towards basic understanding of neurogenesis in the developing brain we have identified novel molecular mechanisms regulating neural stem cell self-renewal and differentiation. In particular, the novel nuclear protein Trnp1 that regulates neural stem cell self-renewal and brain folding, is essential also for conversion of glial cells into neurons, independent of the specific transcription factor used in this conversion process (Masserdotti et al., 2015). We found that Trnp1 acts as a master regulator of nuclear membrane-less organelles by liquid-liquid-phase transition and further unraveled a novel player in regulating neuronal maturation and survival (Ramesh et al., 2016). These discoveries together with identification of novel hurdles in direct reprogramming of glia to neurons allowed us to hugely improve this highly innovative approach for neuronal replacement now achieving more than 90% efficiency in the injured murine brain in vivo (Gascon et al., 2016; Mattugini et al., 2019). Having moved direct reprogramming to such a promising outcome, we turned to another major question, namely to which extent new neurons can adequately integrate when transplanted into an injured brain region that normally does not integrate new neurons. We discovered that this works amazingly well with the new neurons receiving brain-wide only adequate input connectivity and developing their appropriate functional network properties (Falkner, Grade et al., 2016). This grant therefore helped to pave the way towards neuronal replacement therapy and unravel crucial basic mechanisms of neurogenesis.
As research is never fully directed but also often yields surprises, we identified a novel centrosome protein, Akna, that was previously considered a transcription factor and we thought would be a counteracting Trnp1 function. It does indeed counteract Trnp1 function by mediating neural stem cells to leave the stem cell niche and differentiate, but it does so by orchestrating microtubules at the centrosome and thereby weaking junctional coupling to neighboring neural stem cells (Camargo et al., 2019). Most importantly, this mechanism applies not only in the nervous system, but also for other cells leaving an epithelium and may hence pave the way to novel approaches interfering with metastasis formation. These results thus show how investing into basic research leads to pioneering discovery of novel treatment options.