Molecular mechanisms underlying direct conversion of fibroblast to neurons

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The molecular etiologies of many neurological disorders, such as autism or Alzheimers disease, are poorly understood. A major hurdle in the functional study of these diseases is the limited access to human neuronal cells. Therefore, the recent discovery that overexpression of proneural transcription factors can directly convert various cell types into induced neuronal (iN) cells has provided a new and fascinating approach to study and potentially treat neurological diseases. Nevertheless, the full potential of human iN cells for basic research and regenerative medicine will only be realized once we fully understand the reprogramming process at the molecular level and are able to increase the conversion efficiency of human cells (currently around 2%).The aim of this research proposal is to define the molecular mechanisms of iN cell generation using the evolutionary conserved but more efficient mouse model system (conversion efficiency around 20%) in order to understand and improve the reprogramming process for future medical applications. This study will elucidate the hierarchy of the three transcription factors required to convert human and mouse cells (Ascl1, Brn2 and Myt1l), as well as determine the important functional domains of each factor. I will employ biochemical and functional assays to identify and characterize essential interaction partners of the transcription factors and their functional domains, gaining valuable insight into the mechanisms of iN cell reprogramming. Finally, I will use the information from my structure- function and mechanistic studies to design and test synthetic reprogramming factors for their capacity to enhance iN cell conversion efficiencies, e.g. by fusing reprogramming factor domains with interacting transactivators. I am confident that this work will not only improve our understanding of the general mechanisms that govern cell fate switches, but will also help to make human iN formation an efficient and reliable tool, potentially leading to new biomedical applications.