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

doi:10.1083/jcb.200207058

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-talkbetween signaling mechanisms activated by axonal guidance receptors.However, the molecular elements modulated by cyclic nucleotidesin growth cones are not well understood. cGMP is a second messengerwith several distinct targets including cGMP-dependent proteinkinase I (cGKI). Our studies indicated that the ${alpha}$ isoform ofcGKI is predominantly expressed by sensory axons during developmentalstages, whereas most spinal cord neurons are negative for cGKI.Analysis of the trajectories of axons within the spinal cordshowed a longitudinal guidance defect of sensory axons withinthe developing dorsal root entry zone in the absence of cGKI.Consequently, in cGKI-deficient mice, fewer axons grow withinthe dorsal funiculus of the spinal cord, and lamina-specificinnervation, especially by nociceptive sensory neurons, is stronglyreduced as deduced from anti-trkA staining. These axon guidancedefects in cGKI-deficient mice lead to a substantial impairmentin nociceptive flexion reflexes, shown using electrophysiology.In vitro studies revealed that activation of cGKI in embryonicdorsal root ganglia counteracts semaphorin 3A–inducedgrowth cone collapse. Our studies therefore reveal that cGMPsignaling 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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