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

Cell Biology of the Neuron: Polarity, Plasticity and Regeneration, Crete 2011
CNP/cGMP Signaling Regulates Axon Branching and
Growth by Modulating Microtubule Dynamics
Le Ma , Caihong Xia , Zhen Zhao , Zheng Wang
Zilkha Neurogenetic Institute, University of Southern California
The C-type natriuretic peptide (CNP) has been shown recently to positively
regulate axon branching, growth, and guidance via activation of cyclic guanosine
monophosphate (cGMP) signaling in embryonic dorsal root ganglion (DRG)
neurons, but the cellular mechanisms mediating these developmental processes
have not been established. In this study, we provide evidence linking CNP/cGMP
signaling to microtubule dynamics. First, in embryonic DRG neuronal culture,
low doses of the microtubule depolymerization drug nocodazole block
CNP/cGMP-dependent axon branching and growth. Second, based on real time
imaging of EB3-EGFP labeled growing microtubule ends, we found that global
activation of cGMP signaling leads to increased assembly of dynamic
microtubules in DRG growth cones and axons, while local application of CNP
attracts microtubule assembly and reorients microtubule lattice in the growth
cone. To establish the intracellular signaling pathway involved in this regulation,
we studied the microtubule regulator CRMP2 and found that its phosphorylation
can be relieved by cGMP activation and that the unphosphorylated form of
CRMP2 can enhance axon branching and growth. Finally, similar to that of
cGMP activation, over-expression of CRMP2 leads to increased microtubule
dynamics in both COS cells and DRG neurons, and these activities correlate well
with CRMP2 dephosphorylation. Taken together, our study demonstrates a
critical role of microtubule dynamics in CNP/cGMP-dependent regulation of
axonal development, and provides a model to understand the contribution of
dynamic microtubules to axon branching, growth, and guidance.
Presented by: Ma, Le
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