CELL BIOLOGY OF THE NEURON Polarity ... - Tavernarakis Lab

Cell Biology of the Neuron: Polarity, Plasticity and Regeneration, Crete 2011
The Role of Schwann Cell Notch Signalling in
Peripheral Nerve Regeneration
Daniel Wilton 1 , Jie Shen 2 , Dies Meijer 3 , Laura Feltri 4 , Lawrence Wrabetz 4 ,
Rhona Mirsky 5 , Kristjan Jessen 5
1
University College London
2
Centre For Neurologic diseases, Brigham and Women’s hospital, Harvard Med.
Sch, Boston, MA
3
Dept of cell biology and genetics, Erasmus MC, Rotterdam, Netherlands
4
DIBIT, San Rafaele Scientific Inst., Milan, Italy
5
University College London, London, UK
Peripheral nerves, unlike their CNS counterparts, possess the ability to regenerate
following injury and Schwann cell plasticity plays a fundamental role in this
process. As a result of nerve injury and associated Wallerian degeneration,
Schwann cells demyelinate and dedifferentiate to an immature phenotype broadly
similar to that seen in perinatal nerves. This enables them to provide trophic
support to neurons and a permissive surface for regrowing axons. One of the
signals driving demyelination in Schwann cells is Notch (Woodhoo et al., Nature
Neuroscience 12, 839 - 847 (2009)). Notch is down-regulated at the onset of
myelination and suppressed by the pro-myelin transcription factor Krox-20.
Following nerve injury Notch signalling is activated and in its absence
demyelination is delayed; conversely enforced Notch signalling accelerates the
breakdown of myelin.
Here we examined the role of the Schwann cell Notch signalling pathway in
peripheral nerve regeneration. Unexpectedly, we found that inhibition of Notch
signalling prior to crush injury actually increased the rate of subsequent axonal
regeneration and remyelination. This was accompanied by a more rapid return of
motor function as denoted by gait analysis. We show that one of the mechanisms
underlying the negative impact of Notch signalling on regeneration is likely to be
a direct suppression of genes known to be beneficial to regeneration through a
reduced level of c-Jun. These findings demonstrate that Notch signalling in
Schwann cells plays a role in peripheral nerve regeneration and its inhibition is
able to alter the neuronal response to injury and promote a more rapid return of
function.
Presented by: Wilton, Daniel
Poster No 120
Blue Session
202