cGMP-mediated signaling via cGKIalpha is required for the guidance and connectivity of sensory axons.
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.
Schmidt
Hannes
H
Developmental Neurobiology Group, Medical Research Council, Max-Delbrück-Centrum für Molekulare Medizin, Robert-Rössle-Strasse 10, D-13092 Berlin, Germany.
Werner
Matthias
M
Heppenstall
Paul A
PA
Henning
Mechthild
M
Moré
Margret I
MI
Kühbandner
Susanne
S
Lewin
Gary R
GR
Hofmann
Franz
F
Feil
Robert
R
Rathjen
Fritz G
FG
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001369:Axons / Q000502:physiology*; D046508:Culture Techniques; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004558:Electric Stimulation; D004622:Embryo, Mammalian / Q000502:physiology; D005727:Ganglia, Spinal / Q000033:anatomy & histology / Q000378:metabolism; D005838:Genotype; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009475:Neurons, Afferent / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009619:Nociceptors; D020033:Protein Isoforms; D015290:Second Messenger Systems / Q000502:physiology*; D040121:Semaphorin-3A / Q000494:pharmacology; D013116:Spinal Cord / Q000033:anatomy & histology / Q000378:metabolism
D020033:Protein Isoforms; D040121:Semaphorin-3A; D015124:8-Bromo Cyclic Adenosine Monophosphate; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP