Central Nervous System Regeneration Inhibitors and their Intracellular Substrates Michelle Nash & Horia Pribiag & Alyson E. Fournier & Christian Jacobson Received: 14 July 2009 / Accepted: 27 August 2009 / Published online: 19 September 2009 # Humana Press Inc. 2009 Abstract Injury to the central nervous system (CNS) initiates a cascade of responses that is inhibitory to the regeneration of neurons and full recovery. At the site of injury, glial cells conspire with an inhibitory biochemical milieu to construct both physical and chemical barriers that prevent the outgrowth of axons to or beyond the lesion site. These inhibitors include factors derived from myelin, repulsive guidance cues, and chondroitin sulfate proteogly- cans. Each bind receptors on the axon surface to initiating intracellular signaling cascades that ultimately result in cytoskeletal reorganization and growth cone collapse. Here, we present an overview of the molecules, receptors, and signaling pathways that inhibit CNS regeneration, with a particular focus on the intracellular signaling machinery that may function as convergent targets for multiple inhibitory ligands. Keywords Myelin-associated inhibitors . Nerve regeneration . Glial scar . Chondroitin sulfate proteoglycans Following injury to the adult mammalian central nervous system (CNS), axons do not spontaneously regenerate, and functional connections between neurons are not re-established. This failure to regenerate can be partly attributed to an unfavorable CNS environment [1]. The glial scar is a physical barrier that consists primarily of reactive astro- cytes, which plays an important role in blocking axonal regeneration past the site of injury [2]. In addition, factors from the glial scar and from myelin debris create an inhibitory biochemical barrier that actively signals to the surface of regenerating axons to induce growth cone collapse and inhibit axon extension [3]. Several proteins that inhibit neurite outgrowth have been identified, including myelin- associated glycoprotein (MAG), nogo-A, oligodendrocyte- myelin glycoprotein (OMgp), netrin-1, semaphorin4D, ephrinB3, and chondroitin sulfate proteoglycans (CSPGs). Several of these proteins are upregulated by cells that form the glial scar [4], and the remainder are expressed by oligodendrocytes, which form the insulating myelin mem- brane. Although these inhibitory ligands engage multiple distinct receptors on the neuronal cell surface, they signal through overlapping pathways. This review will overview the inhibitory ligands and receptors through which they signal (Fig. 1), and then will focus on recent advances in our understanding of the intracellular signaling machinery activated in response to inhibitors of CNS regeneration. Ligands Associated with CNS Injury The Glial Scar and CSPGs Damage to the CNS initiates a cascade of events that leads to the formation of a glial scar. Following injury, this scar beneficially stabilizes fragile CNS tissue, protects surrounding M. Nash Department of Biology, University of Waterloo, 200 University Avenue West, Waterloo, ON N2L 3G1, Canada H. Pribiag : A. E. Fournier Department of Neurology and Neurosurgery, Montreal Neurological Institute, 3801 Rue University, Montreal, QC H3A 2B4, Canada C. Jacobson (*) Departments of Biology and Mechanical and Mechatronics Engineering, University of Waterloo, 200 University Avenue West, Waterloo, ON N2L 3G1, Canada e-mail: Jacobson@uwaterloo.ca Mol Neurobiol (2009) 40:224–235 DOI 10.1007/s12035-009-8083-y