MAG, myelin and overcoming growth inhibition in the CNS.

Lisa Mckerracher,Kenneth M Rosen

doi:10.3389/fnmol.2015.00051

Abstract

While neurons in the central nervous system (CNS) have the capacity to regenerate their axons after injury, they fail to do so, in part because regeneration is limited by growth inhibitory proteins present in CNS myelin. Myelin-associated glycoprotein (MAG) was the first myelin-derived growth inhibitory protein identified, and its inhibitory activity was initially elucidated in 1994 independently by the Filbin lab and the McKerracher lab using cell-based and biochemical techniques, respectively. Since that time we have gained a wealth of knowledge concerning the numerous growth inhibitory proteins that are present in myelin, and we also have dissected many of the neuronal signaling pathways that act as stop signs for axon regeneration. Here we give an overview of the early research efforts that led to the identification of myelin-derived growth inhibitory proteins, and the importance of this family of proteins for understanding neurotrauma and CNS diseases. We further provide an update on how this knowledge has been translated towards current clinical studies in regenerative medicine.

Highlights

Ramon y Cajal (1991), the Spanish neuroscientist who won the Nobel Prize in Medicine in 1906, first described in detail the frustrated growth response of axons injured in the spinal cord
To better simulate the presentation of Myelin-associated glycoprotein (MAG) to primary neurons, they co-cultured neurons plated onto Chinese hamster ovary (CHO) cells expressing MAG on their surface. They found that neurite outgrowth from cerebellar neurons was inhibited by MAG, an unexpected finding because it was initially believed that MAG promoted neurite outgrowth. When they tested dorsal root ganglion (DRG) neurons, they found that embryonic DRG neurons grew long neurites on the MAG-CHO cells, whereas MAG inhibited neurite outgrowth from neurons isolated from 7 day-old rats (Mukhopadhyay et al, 1994)
These were the first studies to show a developmentally regulated switch in the neuronal response to myelin-derived growth inhibitory proteins, with MAG promoting the growth of embryonic neurons, while blocking axonal extension from postnatal neurons. Extending this line of studies, Filbin’s group went on to show that the developmental switch in growth responsiveness to myelin-MAG was regulated by the endogenous levels of cyclic AMP. They identified a developmental decrease in neuronal cAMP levels and downstream PKA activity that was highly correlated with the change in neuronal responsiveness to MAG as it became an inhibitor of neurite outgrowth

Summary

Introduction

Ramon y Cajal (1991), the Spanish neuroscientist who won the Nobel Prize in Medicine in 1906, first described in detail the frustrated growth response of axons injured in the spinal cord. Advances in our understanding of the control of axonal regeneration have followed from the discovery of growth inhibitory molecules in the CNS, which can signal to block axonal extension. In its most basic form, CNS injury causes the release of fragmented, disrupted myelin, and this myelin debris inhibits neurite outgrowth. Following the description of these inhibitory proteins, the identification of their specific neuronal receptor molecules further increased support for the rather surprising finding that there existed an endogenous neuronal growth inhibition in the CNS. We focus here on the myelin-derived inhibitors (see Figure 1) They are important because myelin is disrupted in both traumatic injury (Richardson et al, 1982) and neurological diseases including multiple sclerosis (Simons et al, 2014) and neurodegenerative disorders (Bartzokis, 2011)

MAG and Inhibition of Neurite Outgrowth

MAG in Myelin and Released from Myelin

Neuronal Receptors for Growth Inhibitory Proteins

Translation to Clinical Studies

Summary