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The Journal of Neuroscience, June 17, 2009, 29(24):7886-7897; doi:10.1523/JNEUROSCI.0087-09.2009

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Cellular/Molecular
The Nitric Oxide–cGMP Pathway Controls the Directional Polarity of Growth Cone Guidance via Modulating Cytosolic Ca²⁺ Signals

Takuro Tojima, ^* Rurika Itofusa, ^* and Hiroyuki Kamiguchi

Laboratory for Neuronal Growth Mechanisms, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan

Correspondence should be addressed to either Hiroyuki Kamiguchi or Takuro Tojima, Laboratory for Neuronal Growth Mechanisms, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan, Email: kamiguchi{at}brain.riken.jp or Email: tojima{at}brain.riken.jp

Asymmetric Ca²⁺ signals across the growth cone mediate attractive or repulsive axon guidance depending on the occurrence of Ca²⁺-induced Ca²⁺ release (CICR) through ryanodine receptors (RyRs). Although the neuronal isoform of nitric oxide (NO) synthase (nNOS) is highly expressed in developing dorsal root ganglion (DRG) neurons, the role of NO in axon guidance remains essentially unknown. Here we report that the NO–cGMP pathway negatively regulates CICR to control the directional polarity of DRG axon guidance. Intracellular levels of NO and cGMP depend on extracellular substrates: laminin activates the NO–cGMP pathway, whereas the adhesion molecule L1 does not. The activity of NO and cGMP determines the turning direction of growth cones with respect to asymmetric Ca²⁺ signals that are produced by photolysing caged Ca²⁺. The Ca²⁺ signals cause growth cone repulsion on a laminin substrate, which is converted to attraction by pharmacological blockade of the NO–cGMP pathway or genetic deletion of nNOS. Conversely, Ca²⁺-induced growth cone attraction on an L1 substrate is converted to repulsion by increasing NO levels. Such NO-mediated switching of turning direction involves the regulation of CICR through RyRs. Furthermore, growth cone repulsion induced by an extracellular gradient of a physiological cue, neurotrophin-4, is dependent on Ca²⁺ signals and converted to attraction by inhibiting the NO–cGMP pathway. These results suggest that, on contact with different adhesive environments, growth cones can change their turning responses to axon guidance cues by modulating CICR via endogenous NO and cGMP.

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Received Jan. 7, 2009; revised April 16, 2009; accepted May 19, 2009.

Correspondence should be addressed to either Hiroyuki Kamiguchi or Takuro Tojima, Laboratory for Neuronal Growth Mechanisms, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan, Email: kamiguchi{at}brain.riken.jp or Email: tojima{at}brain.riken.jp

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