Project Details
Projekt
Deciphering the mRNP Code for Successful Glia to Neuron Reprogramming
Subject Area
General Genetics and Functional Genome Biology
Developmental Biology
Cell Biology
Developmental Biology
Cell Biology
Term
from 2019 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 427451793
The generation of new neurons and their functional integration into damaged neuronal circuits are the major challenges in regenerative medicine upon brain injury and neurodegeneration. A recent, revolutionary approach to convert local, reactive glial cells with the help of neurogenic factors into functionally integrated neurons represented a milestone in restoring neuronal circuitry. As conversion works at surprisingly high rates, this approach is most promising for future regenerative therapies. However, a number of obstacles, including the synaptic integration of new neurons into the pre-existing circuitry, have to be resolved in order to translate these revolutionary discoveries into the clinic.We have recently discovered that the direct conversion of glial cells to neurons requires the RNA-binding proteins (RBPs) Staufen2 (Stau2) and Pumilio2 (Pum2). Moreover, we showed that Stau2 binds two key RNAs coding for Hes1 and Sox11, both representing key neuronal transcription? factors essential for direct glia to neuron conversion. Therefore, we will investigate Stau2 and Pum2 function in implementing neuronal fate by identifying the essential set of RNA targets necessary for direct astrocyte to neuron conversion. Next, we will dissect the role of these RBPs in controlling neurogenic target RNA stability, localization and local translation during the conversion process. Moreover, we will address the specificity (and redundancy) in Stau2 and Pum2 function(s) in fate decision. Finally, we will identify additional key RBPs involved in the functional regulation of Hes1 and Sox11 mRNAs in order to understand the dynamics of mRNP assembly and their functional contribution to direct glia to neuron conversion in detail.We envision that the experiments outlined in this proposal will enable us to initiate novel strategies to improve functional integration of new neurons into damaged circuits and hence explore their potential for regenerative therapies.
DFG Programme
Priority Programmes
