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Published online 4 November 2002. doi:10.1083/jcb.200207058
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© The Rockefeller University Press, 0021-9525/2002/11/489 $5.00
The Journal of Cell Biology, Volume 159, Number 3, 489-498

Article

 cGMP-mediated signaling via cGKI{alpha} is required for the guidance and connectivity of sensory axons

Hannes Schmidt1, Matthias Werner3, Paul A. Heppenstall2, Mechthild Henning1, Margret I. Moré1, Susanne Kühbandner3, Gary R. Lewin2, Franz Hofmann3, Robert Feil3 and Fritz G. Rathjen1

1 Developmental Neurobiology Group, Max-Delbrück-Centrum für Molekulare Medizin, D-13092 Berlin, Germany
2 Growth Factors and Regeneration Group, Max-Delbrück-Centrum für Molekulare Medizin, D-13092 Berlin, Germany
3 Institut für Pharmakologie und Toxikologie, Technische Universität München, D-80802 München, Germany

Address correspondence to Fritz G. Rathjen, Medical Research Council, Robert-Rössle-Str. 10, D-13092 Berlin, Germany. Tel.: 49-30-9406-3709. Fax: 49-30-9406-3730. E-mail: rathjen{at}mdc-berlin.de

Previous in vitro studies using cGMP or cAMP revealed a cross-talk between signaling mechanisms activated by axonal guidance receptors. However, the molecular elements modulated by cyclic nucleotides in growth cones are not well understood. cGMP is a second messenger with several distinct targets including cGMP-dependent protein kinase I (cGKI). Our studies indicated that the {alpha} isoform of cGKI is predominantly expressed by sensory axons during developmental stages, whereas most spinal cord neurons are negative for cGKI. Analysis of the trajectories of axons within the spinal cord showed a longitudinal guidance defect of sensory axons within the developing dorsal root entry zone in the absence of cGKI. Consequently, in cGKI-deficient mice, fewer axons grow within the dorsal funiculus of the spinal cord, and lamina-specific innervation, especially by nociceptive sensory neurons, is strongly reduced as deduced from anti-trkA staining. These axon guidance defects in cGKI-deficient mice lead to a substantial impairment in nociceptive flexion reflexes, shown using electrophysiology. In vitro studies revealed that activation of cGKI in embryonic dorsal root ganglia counteracts semaphorin 3A–induced growth cone collapse. Our studies therefore reveal that cGMP signaling is important for axonal growth in vivo and in vitro.

Key Words: cGMP signaling; axonal pathfinding; cGMP-dependent protein kinase I; sensory axons; nociceptive flexion reflex


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