New neurons after brain injury - from mechanisms to functional integration

Giacomo Masserdotti1,2, Sergio Gascon1,2, Elisa Murenu 1,2, Sofia Grade1,2, Susanne Falkner3, Klaus Conzelmann4, Leda Dimou1,2, Mark Hübener3 and Magdalena Götz1,2

1Institute for Stem Cell Research, Helmholtz Center Munich,  2Biomedical Center, University of Munich, 3 Max-Planck Institute for Neurobiology Martinsried/Munich, 4Max-von-Pettenkofer Institute and Gene Center, University of Munich, Germany

 
The gold standard of understanding a process is to be able to elicit it when it normally does not occur. Already in 2002 we showed that a single neurogenic factor is sufficient to turn glial cells into neurons, and this process of direct neuronal reprogramming has much improved since then. However, the major challenges remaining are a) to determine to which extent new neurons integrate in a neural circuit in a meaningful manner to reestablish functional circuits in brain regions that normally do not undergo neurogenesis. Once I answered this question for new neurons transplanted into the adult mouse visual cortex I will then turn to the main challenges of direct reprogramming – namely to implement this process successfully in the inflammatory environment after brain injury in vivo and to generate specific neuronal subtypes. I will talk first about the mechanisms of neurogenesis and evoking it in cells that normally do not generate neurons in vitro. I discuss in particular unpublished data addressing the molecular events when turning e.g. glial cells into different types of neurons allowing to answer basic principles of establishing cell (in this case neuronal) diversity. I will then move to discuss fundamental aspects of the process of direct conversion of glia or fibroblasts into functional neurons that lead us into the metabolic constraints of this fate conversion. Key factors beyond the classic neurogenic transcription factors shed not only new light on the reprogramming process but also prove to be especially critical in the environment of invasive brain injury in vivo.