Mechanisms of CNS myelin inhibition: Evidence for distinct and neuronal cell type specific receptor systems

Roman J. Giger, Karthik Venkatesh, Onanong Chivatakarn, Stephen J. Raiker, Laurie Robak, Thomas Hofer, Hakjoo Lee, Christoph Rader

Research output: Contribution to journalReview article

62 Citations (Scopus)

Abstract

Following injury to the adult mammalian central nervous system, regenerative growth of severed axons is very limited. The lack of neuronal repair is often associated with significant functional deficits, and depending on the severity of injury, may result in permanent paralysis distal to the site of injury. A detailed understanding of the molecular mechanisms that limit neuronal growth in the injured spinal cord is an important step toward the development of specific strategies aimed at restoring functional connectivity lost as a consequence of injury. While rapid progress is being made in defining the molecular identity of CNS growth inhibitory constituents, comparatively little is known about their receptors and downstream signaling mechanisms. Emerging new evidence suggests that the mechanisms for myelin inhibition are likely to be complex, involving multiple and distinct receptor systems that may operate in a redundant manner. Furthermore, the relative contribution of a specific ligand-receptor system to bring about growth inhibition may greatly vary among different neuronal cell types. Myelin-associated glycoprotein (MAG), for example, employs different mechanisms to inhibit neurite outgrowth of cerebellar, sensory, and retinal ganglion neurons in vitro. Nogo-A harbors distinct growth inhibitory regions, which employ different signaling mechanisms. The Nogo-66 receptor 1 (NgR1), a shared ligand binding component in a receptor complex for Nogo-66, MAG, and OMgp, participates in neuronal growth cone collapse to acutely presented myelin inhibitors, but is dispensable for longitudinal neurite outgrowth inhibition on substrate-bound Nogo-66, MAG, OMgp, or crude CNS myelin in vitro. Consistent with the idea of cell-type specific mechanisms for myelin inhibition, different types of CNS neurons possess very different regenerative capacities and respond differently to experimental treatment strategies in vivo. We speculate that differences in regenerative axonal growth among different fiber systems are a reflection of their intrinsic ability to elongate axons and their distinct cell surface receptor profiles to respond to the growth inhibitory extracellular milieu. The existence of cell type specific mechanisms to impair regenerative axonal growth in the CNS may have important implications for the development of treatment strategies. Depending on the fiber tract injured, different ligand-receptor systems may need to be targeted in order to elicit robust and long-distance regenerative axonal growth.

Original languageEnglish (US)
Pages (from-to)97-115
Number of pages19
JournalRestorative Neurology and Neuroscience
Volume26
Issue number2-3 AXONAL REGENERATO
StatePublished - Oct 1 2008

Fingerprint

Myelin Sheath
Growth
Myelin-Associated Glycoprotein
Wounds and Injuries
Ligands
Axons
Sensory Ganglia
Retinal Neurons
Growth Cones
Cell Surface Receptors
Paralysis
Spinal Cord
Central Nervous System
Neurons

Keywords

  • Ganglioside
  • Integrin
  • Myelin associated glycoprotein
  • NgR1
  • NgR2
  • Nogo-A
  • Receptor
  • Spinal cord injury

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience
  • Clinical Neurology

Cite this

Giger, R. J., Venkatesh, K., Chivatakarn, O., Raiker, S. J., Robak, L., Hofer, T., ... Rader, C. (2008). Mechanisms of CNS myelin inhibition: Evidence for distinct and neuronal cell type specific receptor systems. Restorative Neurology and Neuroscience, 26(2-3 AXONAL REGENERATO), 97-115.

Mechanisms of CNS myelin inhibition : Evidence for distinct and neuronal cell type specific receptor systems. / Giger, Roman J.; Venkatesh, Karthik; Chivatakarn, Onanong; Raiker, Stephen J.; Robak, Laurie; Hofer, Thomas; Lee, Hakjoo; Rader, Christoph.

In: Restorative Neurology and Neuroscience, Vol. 26, No. 2-3 AXONAL REGENERATO, 01.10.2008, p. 97-115.

Research output: Contribution to journalReview article

Giger, RJ, Venkatesh, K, Chivatakarn, O, Raiker, SJ, Robak, L, Hofer, T, Lee, H & Rader, C 2008, 'Mechanisms of CNS myelin inhibition: Evidence for distinct and neuronal cell type specific receptor systems', Restorative Neurology and Neuroscience, vol. 26, no. 2-3 AXONAL REGENERATO, pp. 97-115.
Giger RJ, Venkatesh K, Chivatakarn O, Raiker SJ, Robak L, Hofer T et al. Mechanisms of CNS myelin inhibition: Evidence for distinct and neuronal cell type specific receptor systems. Restorative Neurology and Neuroscience. 2008 Oct 1;26(2-3 AXONAL REGENERATO):97-115.
Giger, Roman J. ; Venkatesh, Karthik ; Chivatakarn, Onanong ; Raiker, Stephen J. ; Robak, Laurie ; Hofer, Thomas ; Lee, Hakjoo ; Rader, Christoph. / Mechanisms of CNS myelin inhibition : Evidence for distinct and neuronal cell type specific receptor systems. In: Restorative Neurology and Neuroscience. 2008 ; Vol. 26, No. 2-3 AXONAL REGENERATO. pp. 97-115.
@article{cb9c4edd9937489e82a7b4026a0889a5,
title = "Mechanisms of CNS myelin inhibition: Evidence for distinct and neuronal cell type specific receptor systems",
abstract = "Following injury to the adult mammalian central nervous system, regenerative growth of severed axons is very limited. The lack of neuronal repair is often associated with significant functional deficits, and depending on the severity of injury, may result in permanent paralysis distal to the site of injury. A detailed understanding of the molecular mechanisms that limit neuronal growth in the injured spinal cord is an important step toward the development of specific strategies aimed at restoring functional connectivity lost as a consequence of injury. While rapid progress is being made in defining the molecular identity of CNS growth inhibitory constituents, comparatively little is known about their receptors and downstream signaling mechanisms. Emerging new evidence suggests that the mechanisms for myelin inhibition are likely to be complex, involving multiple and distinct receptor systems that may operate in a redundant manner. Furthermore, the relative contribution of a specific ligand-receptor system to bring about growth inhibition may greatly vary among different neuronal cell types. Myelin-associated glycoprotein (MAG), for example, employs different mechanisms to inhibit neurite outgrowth of cerebellar, sensory, and retinal ganglion neurons in vitro. Nogo-A harbors distinct growth inhibitory regions, which employ different signaling mechanisms. The Nogo-66 receptor 1 (NgR1), a shared ligand binding component in a receptor complex for Nogo-66, MAG, and OMgp, participates in neuronal growth cone collapse to acutely presented myelin inhibitors, but is dispensable for longitudinal neurite outgrowth inhibition on substrate-bound Nogo-66, MAG, OMgp, or crude CNS myelin in vitro. Consistent with the idea of cell-type specific mechanisms for myelin inhibition, different types of CNS neurons possess very different regenerative capacities and respond differently to experimental treatment strategies in vivo. We speculate that differences in regenerative axonal growth among different fiber systems are a reflection of their intrinsic ability to elongate axons and their distinct cell surface receptor profiles to respond to the growth inhibitory extracellular milieu. The existence of cell type specific mechanisms to impair regenerative axonal growth in the CNS may have important implications for the development of treatment strategies. Depending on the fiber tract injured, different ligand-receptor systems may need to be targeted in order to elicit robust and long-distance regenerative axonal growth.",
keywords = "Ganglioside, Integrin, Myelin associated glycoprotein, NgR1, NgR2, Nogo-A, Receptor, Spinal cord injury",
author = "Giger, {Roman J.} and Karthik Venkatesh and Onanong Chivatakarn and Raiker, {Stephen J.} and Laurie Robak and Thomas Hofer and Hakjoo Lee and Christoph Rader",
year = "2008",
month = "10",
day = "1",
language = "English (US)",
volume = "26",
pages = "97--115",
journal = "Restorative Neurology and Neuroscience",
issn = "0922-6028",
publisher = "IOS Press",
number = "2-3 AXONAL REGENERATO",

}

TY - JOUR

T1 - Mechanisms of CNS myelin inhibition

T2 - Evidence for distinct and neuronal cell type specific receptor systems

AU - Giger, Roman J.

AU - Venkatesh, Karthik

AU - Chivatakarn, Onanong

AU - Raiker, Stephen J.

AU - Robak, Laurie

AU - Hofer, Thomas

AU - Lee, Hakjoo

AU - Rader, Christoph

PY - 2008/10/1

Y1 - 2008/10/1

N2 - Following injury to the adult mammalian central nervous system, regenerative growth of severed axons is very limited. The lack of neuronal repair is often associated with significant functional deficits, and depending on the severity of injury, may result in permanent paralysis distal to the site of injury. A detailed understanding of the molecular mechanisms that limit neuronal growth in the injured spinal cord is an important step toward the development of specific strategies aimed at restoring functional connectivity lost as a consequence of injury. While rapid progress is being made in defining the molecular identity of CNS growth inhibitory constituents, comparatively little is known about their receptors and downstream signaling mechanisms. Emerging new evidence suggests that the mechanisms for myelin inhibition are likely to be complex, involving multiple and distinct receptor systems that may operate in a redundant manner. Furthermore, the relative contribution of a specific ligand-receptor system to bring about growth inhibition may greatly vary among different neuronal cell types. Myelin-associated glycoprotein (MAG), for example, employs different mechanisms to inhibit neurite outgrowth of cerebellar, sensory, and retinal ganglion neurons in vitro. Nogo-A harbors distinct growth inhibitory regions, which employ different signaling mechanisms. The Nogo-66 receptor 1 (NgR1), a shared ligand binding component in a receptor complex for Nogo-66, MAG, and OMgp, participates in neuronal growth cone collapse to acutely presented myelin inhibitors, but is dispensable for longitudinal neurite outgrowth inhibition on substrate-bound Nogo-66, MAG, OMgp, or crude CNS myelin in vitro. Consistent with the idea of cell-type specific mechanisms for myelin inhibition, different types of CNS neurons possess very different regenerative capacities and respond differently to experimental treatment strategies in vivo. We speculate that differences in regenerative axonal growth among different fiber systems are a reflection of their intrinsic ability to elongate axons and their distinct cell surface receptor profiles to respond to the growth inhibitory extracellular milieu. The existence of cell type specific mechanisms to impair regenerative axonal growth in the CNS may have important implications for the development of treatment strategies. Depending on the fiber tract injured, different ligand-receptor systems may need to be targeted in order to elicit robust and long-distance regenerative axonal growth.

AB - Following injury to the adult mammalian central nervous system, regenerative growth of severed axons is very limited. The lack of neuronal repair is often associated with significant functional deficits, and depending on the severity of injury, may result in permanent paralysis distal to the site of injury. A detailed understanding of the molecular mechanisms that limit neuronal growth in the injured spinal cord is an important step toward the development of specific strategies aimed at restoring functional connectivity lost as a consequence of injury. While rapid progress is being made in defining the molecular identity of CNS growth inhibitory constituents, comparatively little is known about their receptors and downstream signaling mechanisms. Emerging new evidence suggests that the mechanisms for myelin inhibition are likely to be complex, involving multiple and distinct receptor systems that may operate in a redundant manner. Furthermore, the relative contribution of a specific ligand-receptor system to bring about growth inhibition may greatly vary among different neuronal cell types. Myelin-associated glycoprotein (MAG), for example, employs different mechanisms to inhibit neurite outgrowth of cerebellar, sensory, and retinal ganglion neurons in vitro. Nogo-A harbors distinct growth inhibitory regions, which employ different signaling mechanisms. The Nogo-66 receptor 1 (NgR1), a shared ligand binding component in a receptor complex for Nogo-66, MAG, and OMgp, participates in neuronal growth cone collapse to acutely presented myelin inhibitors, but is dispensable for longitudinal neurite outgrowth inhibition on substrate-bound Nogo-66, MAG, OMgp, or crude CNS myelin in vitro. Consistent with the idea of cell-type specific mechanisms for myelin inhibition, different types of CNS neurons possess very different regenerative capacities and respond differently to experimental treatment strategies in vivo. We speculate that differences in regenerative axonal growth among different fiber systems are a reflection of their intrinsic ability to elongate axons and their distinct cell surface receptor profiles to respond to the growth inhibitory extracellular milieu. The existence of cell type specific mechanisms to impair regenerative axonal growth in the CNS may have important implications for the development of treatment strategies. Depending on the fiber tract injured, different ligand-receptor systems may need to be targeted in order to elicit robust and long-distance regenerative axonal growth.

KW - Ganglioside

KW - Integrin

KW - Myelin associated glycoprotein

KW - NgR1

KW - NgR2

KW - Nogo-A

KW - Receptor

KW - Spinal cord injury

UR - http://www.scopus.com/inward/record.url?scp=52649100458&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=52649100458&partnerID=8YFLogxK

M3 - Review article

C2 - 18820405

AN - SCOPUS:52649100458

VL - 26

SP - 97

EP - 115

JO - Restorative Neurology and Neuroscience

JF - Restorative Neurology and Neuroscience

SN - 0922-6028

IS - 2-3 AXONAL REGENERATO

ER -