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      cGMP-mediated signaling via cGKIα is required for the guidance and connectivity of sensory axons

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          Abstract

          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 α 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.

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          Most cited references47

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          The molecular biology of axon guidance.

          Neuronal growth cones navigate over long distances along specific pathways to find their correct targets. The mechanisms and molecules that direct this pathfinding are the topics of this review. Growth cones appear to be guided by at least four different mechanisms: contact attraction, chemoattraction, contact repulsion, and chemorepulsion. Evidence is accumulating that these mechanisms act simultaneously and in a coordinated manner to direct pathfinding and that they are mediated by mechanistically and evolutionarily conserved ligand-receptor systems.
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            Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones.

            Repulsive guidance cues can steer neuronal growth cones during development and prevent mature axons from regenerating. We have identified a 100 kd glycoprotein in the chick brain that is a good candidate for a repulsive cue. Since it induces the collapse and paralysis of neuronal growth cones in vitro, we have named it collapsin. It is effective at concentrations of approximately 10 pM. The C-terminal half of collapsin contains a single immunoglobulin-like domain and an additional highly basic region. The N-terminal half of collapsin shares significant homology with fasciclin IV, a growth cone guidance protein in grasshopper. Recombinant collapsin causes sensory ganglion growth cones to collapse but not retinal ganglion cell growth cones. We propose that collapsin could serve as a ligand that guides specific growth cones by a motility-inhibiting mechanism.
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              Guanylyl cyclases and signaling by cyclic GMP.

              Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types. They are regulated by diverse extracellular agonists that include peptide hormones, bacterial toxins, and free radicals, as well as intracellular molecules, such as calcium and adenine nucleotides. Stimulation of guanylyl cyclases and the resultant accumulation of cGMP regulates complex signaling cascades through immediate downstream effectors, including cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cyclic nucleotide-gated ion channels. Guanylyl cyclases and cGMP-mediated signaling cascades play a central role in the regulation of diverse (patho)physiological processes, including vascular smooth muscle motility, intestinal fluid and electrolyte homeostasis, and retinal phototransduction. Topics addressed in this review include the structure and chromosomal localization of the genes for guanylyl cyclases, structure and function of the members of the guanylyl cyclase family, molecular mechanisms regulating enzymatic activity, and molecular sequences coupling ligand binding to catalytic activity. A brief overview is presented of the downstream events controlled by guanylyl cyclases, including the effectors that are regulated by cGMP and the role that guanylyl cyclases play in cell physiology and pathophysiology.
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                Author and article information

                Journal
                J Cell Biol
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                11 November 2002
                : 159
                : 3
                : 489-498
                Affiliations
                [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
                Author notes

                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@ 123456mdc-berlin.de

                Article
                200207058
                10.1083/jcb.200207058
                2173065
                12417579
                20aea491-eb8c-4079-a913-608c7fafb922
                Copyright © 2002, The Rockefeller University Press
                History
                : 10 July 2002
                : 23 September 2002
                : 24 September 2002
                Categories
                Article

                Cell biology
                cgmp signaling; axonal pathfinding; cgmp-dependent protein kinase i; sensory axons; nociceptive flexion reflex

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