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.