[en] The neural scar that forms after injury to the mammalian central nervous system is a barrier to sprouting and regenerating axons. In addition to reactive astrocytes that are present throughout the lesion site, leptomeningeal fibroblasts invade the lesion core. When isolated in vitro, these cells form a very poor substrate for growing neurites, even more so than reactive astrocytes. Nevertheless the molecular mechanisms involved in this growth inhibition are not well understood. Semaphorins have been reported to be upregulated in meningeal cells (MCs) on mechanical injury to the brain and spinal cord. In the present study, we show that Sema3A mRNA and active protein are produced by cultured meningeal cells. A protein extract from these cells induces the collapse of embryonic dorsal root ganglion (DRG) growth cones. This collapsing activity is partially blocked by neuropilin-1 antibodies and is absent in meningeal cells derived from Sema3A-knockout mice. In addition to growth cone collapse, recombinant Sema3A but not Sema3C inhibits neurite outgrowth of embryonic DRGs. Consistent with this result we find that the inhibitory effect of meningeal cells on neurite outgrowth is partially overcome on Sema3A-deficient MCs. Furthermore we show that the inhibitory effect of MC-derived Sema3A on neurite outgrowth is modulated by nerve growth factor. Our results show that Sema3A, a chemorepellent during nervous system development, is a major neurite growth-inhibitory molecule in meningeal fibroblasts and is therefore likely to contribute to the inhibitory properties of the neural scar.
Disciplines :
Oncologie
Auteur, co-auteur :
NICLOU, Simone P. ; Graduate School of Neurosciences Amsterdam, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands. s.niclou@nih.knaw.nl
Abnet K., Fawcett J.W., Dunnett S.B. Interactions between meningeal cells and astrocytes in vivo and in vitro. Brain Res. Dev. Brain Res. 59:1991;187-196.
Asher R.A., Morgenstern D.A., Shearer M.C., Adcock K.H., Pesheva P., Fawcett J.W. Versican is upregulated in CNS injury and is a product of oligodendrocyte lineage cells. J. Neurosci. 22:2002;2225-2236.
Avnur Z., Geiger B. Immunocytochemical localization of native chondroitin-sulfate in tissues and cultured cells using specific monoclonal antibody. Cell. 38:1984;811-822.
Bagnard D., Thomasset N., Lohrum M., Puschel A.W., Bolz J. Spatial distributions of guidance molecules regulate chemorepulsion and chemoattraction of growth cones. J. Neurosci. 20:2000;1030-1035.
Berggren K., McCaffery P., Drager U., Forehand C.J. Differential distribution of retinoic acid synthesis in the chicken embryo as determined by immunolocalization of the retinoic acid synthetic enzyme, RALDH-2. Dev. Biol. 210:1999;288-304.
Berry M., Maxwell W.L., Logan A., Mathewson A., McConnell P., Ashhurst D.E., Thomas G.H. Deposition of scar tissue in the central nervous system. Acta Neurochir. Suppl. (Wien). 32:1983;31-53.
Cai D., Shen Y., De Bellard M., Tang S., Filbin M.T. Prior exposure to neurotrophins blocks inhibition of axonal regeneration by MAG and myelin via a cAMP-dependent mechanism. Neuron. 22:1999;89-101.
Carbonell A.L., Boya J. Ultrastructural study on meningeal regeneration and meningo-glial relationships after cerebral stab wound in the adult rat. Brain Res. 439:1988;337-344.
Chalasani S.H., Sabelko K.A., Sunshine M.J., Littman D.R., Raper J.A. A chemokine, SDF-1, reduces the effectiveness of multiple axonal repellents and is required for normal axon pathfinding. J. Neurosci. 23:2003;1360-1371.
Chen H., Chedotal A., He Z., Goodman C.S., Tessier-Lavigne M. Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III. Neuron. 19:1997;547-559.
Chen H., He Z., Bagri A., Tessier-Lavigne M. Semaphorin-neuropilin interactions underlying sympathetic axon responses to class III semaphorins. Neuron. 21:1998;1283-1290.
Davies S.J., Goucher D.R., Doller C., Silver J. Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord. J. Neurosci. 19:1999;5810-5822.
Dergham P., Ellezam B., Essagian C., Avedissian H., Lubell W.D., McKerracher L. Rho signaling pathway targeted to promote spinal cord repair. J. Neurosci. 22:2002;6570-6577.
De Winter F., Holtmaat A.J., Verhaagen J. Neuropilin and class 3 semaphorins in nervous system regeneration. Adv. Exp. Med. Biol. 515:2002;115-139.
De Winter F., Oudega M., Lankhorst A.J., Hamers F.P., Blits B., Ruitenberg M.J., Pasterkamp R.J., Gispen W.H., Verhaagen J. Injury-induced class 3 semaphorin expression in the rat spinal cord. Exp. Neurol. 175:2002;61-75.
Dontchev V.D., Letourneau P.C. Nerve growth factor and semaphorin 3A signaling pathways interact in regulating sensory neuronal growth cone motility. J. Neurosci. 22:2002;6659-6669.
Fawcett J.W., Asher R.A. The glial scar and central nervous system repair. Brain Res. Bull. 49:1999;377-391.
Gavazzi I., Stonehouse J., Sandvig A., Reza J.N., Appiah-Kubi L.S., Keynes R., Cohen J. Peripheral, but not central, axotomy induces neuropilin-1 mRNA expression in adult large diameter primary sensory neurons. J. Comp Neurol. 423:2000;492-499.
Giger R.J., Pasterkamp R.J., Heijnen S., Holtmaat A.J., Verhaagen J. Anatomical distribution of the chemorepellent semaphorin III/collapsin-1 in the adult rat and human brain predominant expression in structures of the olfactory-hippocampal pathway and the motor system . J. Neurosci. Res. 52:1998;27-42.
Hermanns S., Klapka N., Muller H.W. The collagenous lesion scar an obstacle for axonal regeneration in brain and spinal cord injury . Restor. Neurol. Neurosci. 19:2001;139-148.
Hirsch S., Bahr M. Immunocytochemical characterization of reactive optic nerve astrocytes and meningeal cells. Glia. 26:1999;36-46.
Holtmaat A.J., De Winter F., De Wit J., Gorter J.A., da Silva F.H., Verhaagen J. Semaphorins contributors to structural stability of hippocampal networks . Prog. Brain Res. 138:2002;17-38.
Holtmaat A.J., Gorter J.A., De Wit J., Tolner E.A., Spijker S., Giger R.J., Lopes da Silva F.H., Verhaagen J. Transient downregulation of Sema3A mRNA in a rat model for temporal lobe epilepsy. A novel molecular event potentially contributing to mossy fiber sprouting. Exp. Neurol. 182(1):2003;142-150.
Kapfhammer J.P., Grunewald B.E., Raper J.A. The selective inhibition of growth cone extension by specific neurites in culture. J. Neurosci. 6:1986;2527-2534.
Kolodkin A.L., Levengood D.V., Rowe E.G., Tai Y.T., Giger R.J., Ginty D.D. Neuropilin is a semaphorin III receptor. Cell. 90:1997;753-762.
Koppel A.M., Feiner L., Kobayashi H., Raper J.A. A 70 amino acid region within the semaphorin domain activates specific cellular response of semaphorin family members. Neuron. 19:1997;531-537.
Lehmann M., Fournier A., Selles-Navarro I., Dergham P., Sebok A., Leclerc N., Tigyi G., McKerracher L. Inactivation of Rho signaling pathway promotes CNS axon regeneration. J. Neurosci. 19:1999;7537-7547.
Loschinger J., Weth F., Bonhoeffer F. Reading of concentration gradients by axonal growth cones. Philos. Trans. R. Soc. London Ser. B. 355:2000;971-982.
Luo L. Rho GTPases in neuronal morphogenesis. Nat. Rev. Neurosci. 1:2000;173-180.
Luo Y., Raible D., Raper J.A. Collapsin a protein in brain that induces the collapse and paralysis of neuronal growth cones . Cell. 75:1993;217-227.
Miyazaki N., Furuyama T., Amasaki M., Sugimoto H., Sakai T., Takeda N., Kubo T., Inagaki S. Mouse semaphorin H inhibits neurite outgrowth from sensory neurons. Neurosci. Res. 33:1999;269-274.
Miyazaki N., Furuyama T., Sakai T., Fujioka S., Mori T., Ohoka Y., Takeda N., Kubo T., Inagaki S. Developmental localization of semaphorin H messenger RNA acting as a collapsing factor on sensory axons in the mouse brain. Neuroscience. 93:1999;401-408.
Moon L.D., Asher R.A., Rhodes K.E., Fawcett J.W. Regeneration of CNS axons back to their target following treatment of adult rat brain with chondroitinase ABC. Nat. Neurosci. 4:2001;465-466.
Morgenstern D.A., Asher R.A., Fawcett J.W. Chondroitin sulphate proteoglycans in the CNS injury response. Prog. Brain Res. 137:2002;313-332.
Murakami Y., Suto F., Shimizu M., Shinoda T., Kameyama T., Fujisawa H. Differential expression of plexin-A subfamily members in the mouse nervous system. Dev. Dyn. 220:2001;246-258.
Ness R., David S. Leptomeningeal cells modulate the neurite growth promoting properties of astrocytes in vitro. Glia. 19:1997;47-57.
Neumann S., Bradke F., Tessier-Lavigne M., Basbaum A.I. Regeneration of sensory axons within the injured spinal cord induced by intraganglionic cAMP elevation. Neuron. 34:2002;885-893.
Niederost B., Oertle T., Fritsche J., McKinney R.A., Bandtlow C.E. Nogo-A and myelin-associated glycoprotein mediate neurite growth inhibition by antagonistic regulation of RhoA and Racl. J. Neurosci. 22:2002;10368-10376.
Noble M., Fok-Seang J., Cohen J. Glia are a unique substrate for the in vitro growth of central nervous system neurons. J. Neurosci. 4:1984;1892-1903.
Owesson C., Pizzey J., Tonge D. Sensitivity of NGF-responsive dorsal root ganglion neurons to semaphorin D is maintained in both neonatal and adult mice. Exp. Neurol. 165:2000;394-398.
Pasterkamp R.J., De Winter F., Holtmaat A.J., Verhaagen J. Evidence for a role of the chemorepellent semaphorin III and its receptor neuropilin-1 in the regeneration of primary olfactory axons. J. Neurosci. 18:1998;9962-9976.
Pasterkamp R.J., Giger R.J., Ruitenberg M.J., Holtmaat A.J., De Wit J., De Winter F., Verhaagen J. Expression of the gene encoding the chemorepellent semaphorin III is induced in the fibroblast component of neural scar tissue formed following injuries of adult but not neonatal CNS. Mol. Cell Neurosci. 13:1999;143-166.
Qiu J., Cai D., Dai H., McAtee M., Hoffman P.N., Bregman B.S., Filbin M.T. Spinal axon regeneration induced by elevation of cyclic AMP. Neuron. 34:2002;895-903.
Raper J.A. Semaphorins and their receptors in vertebrates and invertebrates. Curr. Opin. Neurobiol. 10:2000;88-94.
Reier P.J., Lawrence F.E., Jakeman L. Reactive astrocyte and axonal outgrowth in the injured CNS is gliosis really an impediment to regeneration . Seil F.J. Frontiers of Clinical Neuroscience. 1989;183-209 Alan R. Liss, New York.
Reza J.N., Gavazzi I., Cohen J. Neuropilin-1 is expressed on adult mammalian dorsal root ganglion neurons and mediates semaphorin3a/collapsin-1- induced growth cone collapse by small diameter sensory afferents. Mol. Cell Neurosci. 14:1999;317-326.
Ross R. The fibroblast and wound repair. Biol. Rev. Camb. Philos. Soc. 43:1968;51-96.
Rudge J.S., Silver J. Inhibition of neurite outgrowth on astroglial scars in vitro. J. Neurosci. 10:1990;3594-3603.
Shearer M.C., Fawcett J.W. The astrocyte/meningeal cell interface - a barrier to successful nerve regeneration. Cell Tissue Res. 305(2):2001;267-273.
Shearer, M.C., Niclou, S.P., Brown, D., Asher, R.A., Holtmaat, A.J., Verhaagen, J., Fawcett, J.W. The astrocyte/meningeal cell interface is a barrier to neurite outgrowth which can be overcome by manipulation of inhibitory molecules or axonal signalling pathways (submitted).
Sievers J., Pehlemann F.W., Gude S., Berry M. Meningeal cells organize the superficial glia limitans of the cerebellum and produce components of both the interstitial matrix and the basement membrane. J. Neurocytol. 23:1994;135-149.
Song H., Ming G., He Z., Lehmann M., McKerracher L., Tessier-Lavigne M., Poo M. Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science. 281:1998;1515-1518.
Spencer T., Domeniconi M., Cao Z., Filbin M.T. New roles for old proteins in adult CNS axonal regeneration. Curr. Opin. Neurobiol. 13:2003;133-139.
Steward O., Schauwecker P.E., Guth L., Zhang Z., Fujiki M., Inman D., Wrathall J., Kempermann G., Gage F.H., Saatman K.E., Raghupathi R., McIntosh T. Genetic approaches to neurotrauma research opportunities and potential pitfalls of murine models . Exp. Neurol. 157:1999;19-42.
Stichel C.C., Hermanns S., Luhmann H.J., Lausberg F., Niermann H., D'Urso D., Servos G., Hartwig H.G., Muller H.W. Inhibition of collagen IV deposition promotes regeneration of injured CNS axons. Eur. J. Neurosci. 11:1999;632-646.
Stichel C.C., Niermann H., D'Urso D., Lausberg F., Hermanns S., Muller H.W. Basal membrane-depleted scar in lesioned CNS characteristics and relationships with regenerating axons . Neuroscience. 93:1999;321-333.
Tanelian D.L., Barry M.A., Johnston S.A., Le T., Smith G.M. Semaphorin III can repulse and inhibit adult sensory afferents in vivo. Nat. Med. 3:1997;1398-1401.
Taniguchi M., Yuasa S., Fujisawa H., Naruse I., Saga S., Mishina M., Yagi T. Disruption of semaphorin III/D gene causes severe abnormality in peripheral nerve projection. Neuron. 19:1997;519-530.
Tuttle R., O'Leary D.D. Neurotrophins rapidly modulate growth cone response to the axon guidance molecule, collapsin-1. Mol. Cell Neurosci. 11:1998;1-8.
Wang X., Chun S.J., Treloar H., Vartanian T., Greer C.A., Strittmatter S.M. Localization of Nogo-A and Nogo-66 receptor proteins at sites of axon-myelin and synaptic contact. J. Neurosci. 22:2002;5505-5515.
Zhao D., McCaffery P., Ivins K.J., Neve R.L., Hogan P., Chin W.W., Drager U.C. Molecular identification of a major retinoic-acid-synthesizing enzyme, a retinaldehyde-specific dehydrogenase. Eur. J. Biochem. 240:1996;15-22.
