연사 : 조용철 박사 (Washington University in St. Louis)

장소 : 생명과학관 ( 녹지 ) 109 호

제목 : Cellular “Hot-Line” from injury site to command center for nerve regeneration


Abstract

 

Neurons in the peripheral nervous system can successfully activate signal transduction to enable axon regeneration after axonal injury. Injured axons can re-constitute growth-cone-like structures and activate gene transcription required for regeneration. However, neurons within the central nervous system (CNS) typically fail to do these jobs, which leads to permanent functional disorders. Thus, understanding mechanisms recognizing axonal injury and activating regeneration will give us novel therapeutic approaches to improve recovery following axon injury. The unfavorable environments have been thought as the most important factor for poor regenerative capacity of neurons in CNS. However, several recent researches showed that elimination of inhibitory molecules in CNS could make only limited enhancement of regeneration after injury. These results emphasize not only that reducing the inhibitory molecules is not enough to enhance regeneration but also that intrinsic signal transduction of neurons after injury is more important for successful recovery. We found that axonal injury triggers high calcium ion flux in the axon, which propagates back from the site of injury to the cell body. The rapid increment of axonal calcium ion activates protein kinase C (PKC) at the local site of injury in dorsal root ganglion (DRG) neurons. We found that PKC-pathway finally induces phosphorylation of HDAC5 at the axons, which leads to microtubule deacetylation in sciatic nerve. HDAC5-mediated tubulin modification is required for axon regeneration to modulate dynamics of microtubule after injury in PNS. Neurons in CNS fail to do this process, which potentially suggests that limited capacity of regeneration of CNS neurons can be due to the failure of altering microtubule dynamics after injury. We further studied to find the answer how the cell body can recognize injury that happens far away from the cell body. We focused the back-propagation of high calcium influx at the cell body. High concentration of calcium ion induces PKC activation at the neuronal cell body, leads to phosphorylation of HDAC5. Phosphorylated HDAC5 is exported out from the nucleus to the axons. This causes the change of balance between histone acetyltransferases and histone deacetylases and induces hyper-acetylation of histone H3. Finally, genes required for axon regeneration can be activated by specific transcription factors. These new findings give us better understanding how neurons recognize injury and prepare to activate gene expression for regeneration after injury. From this project, we are expanding our questions to ask how regeneration-associated genes are tightly and temporally regulated by specific sets of transcription factors.