The role of local translation in axonal regeneration

In the adult CNS the environment becomes inhibitory to regeneration of adult neurons but not of young ones. Thus, reprogramming neurons back to a developmental state should enable regeneration. While the importance of “nuclear reprogramming” cannot be overstated, the assumption that transcription is the master switch of gene expression should be laid to rest. Regulation of mRNA translatability is also crucial for neurogenesis and neuronal plasticity. Translational control offers a means to spatially and temporally compartmentalize protein function and to fast and effectively change the architecture of local protein complexes. We speculate that local protein synthesis may underlie the initial regenerative response observed following injury to the CNS. Further, we hypothesize that the population of “dormant” mRNAs activated during axonal regeneration may as well get activated during neurogenesis. We plan to identify these “dormant mRNAs”, by a translational state array analysis (TSAA) of the spinal cord and brain at early time points after injury. Thereafter, their role in regeneration and neurogenesis will be assessed in vitro in neural stem cells (NSCs) and laser-axotomy models, and in vivo in animal models of spinal cord injury and neurogenesis. In parallel, we will develop an integrated bioinformatics approach for “in-silico” identification of elements involved in their translational regulation. Found regulatory elements will be further validated in vitro and in vivo. Comparison of regulatory elements in NSCs and regenerating axons may help identifying components missing or defective in adult neurons where activation of local translation seems to be rate limiting. The ultimate goal of this project is to coax axons towards regeneration.

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