Ann Neurol. [1, 2]. Understanding the basis of recovery, as well as the systems that limit growth in the CNS, has been the goal of a century of research. While our understanding remains incomplete, myriad studies have described how injured neurons can be stimulated to grow, overcome physical and chemical barriers, and make functional connections. Here we focus on studies demonstrating the role of myelin-associated inhibitors (MAIs) in restricting axonal growth in the CNS with particular emphasis on the Nogo-Nogo Receptor axis. Pioneering work exhibited that MAIs inhibit axonal regeneration; however, their physiological role remained unclear. Importantly, when MAIs have been antagonized in animal models of SCI, functional recovery exceeds frank axonal regeneration and and enhanced corticospinal tract (CST) Rabbit Polyclonal to FRS2 axon regeneration after a spinal cord injury in young rats. Using peptide sequence information from the IN-1 antibodies, three impartial groups indentified the mammalian gene, Nogo, or Reticulon 4 (Rtn4) [12C14]. Nogo is usually differentially spliced into two isoforms, Nogo A and B; Nogo C is the product of an alternate promoter[12, 13]. All isoforms share a common C-terminal domain name with reticulon homology[12, 13] and hence belong to the reticulon family. Nogo-A is the theory isoform of CNS Nogo, and its expression in the CNS, but not PNS[15, 16], suggests that Nogo-A may account for limited CNS regeneration. Nogo-A is usually predominantly expressed by oligodendrocytes[15, 16], although Nogo-A can also be detected in neurons[15C18]. Using immunoelectron microscopy in oligodendrocytes, Nogo-A has been localized to the innermost and outermost myelin membranes Eltrombopag Olamine as well as the endoplasmic reticulum[15, 16]. Neuronal expression of Nogo-A has been detected in various subsets of mature CNS Eltrombopag Olamine neurons[15C18], and interestingly, at both the pre and post-synaptic side of hippocampal synapses[15, 19]. The localization of Nogo-A at both the periaxonal sheath and synapses suggests functions for Eltrombopag Olamine Nogo-A in both axonal growth and synaptic plasticity. The carboxyl segment of Nogo-A shares homology with reticulon family proteins and contains the hydrophilic 66-amino acid segment (Nogo-66) between two hydrophobic domains (Physique 1). The amino terminus of Nogo-A (amino-Nogo) does not share sequence homology with the reticulon family or with other proteins. Interestingly, both the hydrophilic amino-Nogo and the Nogo-66 domains Eltrombopag Olamine potently inhibit neurite outgrowth through biochemically distinct mechanisms[12C14, 20, 21]. Amino-Nogo disrupts integrin function whereas Nogo-66 inhibits growth through its neuronal receptors, NgR1 and PirB[20, 23]. Subsequent studies have exhibited that both amino-Nogo and Nogo-66 are localized both intracellularly and extracellularly, suggesting multiple topologies for Nogo-A[13, 21] that provide an explanation for how both domains might inhibit growth. Nogo-A has been repeatedly shown to initiate growth cone collapse and inhibit neurite outgrowth by a wide number of laboratories[12C14], and to limit regeneration of the CST after spinal cord injury in mammalian animal models using genetic deletion, neutralizing antibodies, and pharmacologic antagonists and reports of Nogo-A-dependent growth inhibition, suggesting a causal role for Nogo-A in restricting growth in the CNS. Even though and models have pointed to the importance of Nogo-A in limiting regeneration and recovery after SCI, data from Nogo-A deletion mutants has been less simple to interpret. Three impartial laboratories created Nogo-A, Nogo-A/B, and Nogo-A/B/C mutants, with varying regeneration phenotypes[26, 27, 32, 33]. Subsequent studies have exhibited that age, strain, and type of lesion also modulate the Nogo null phenotype, complicating the interpretation of the data from the three different deletion mutants. Ongoing studies are characterizing a compensatory genetic difference (our unpublished observations) between two Nogo-A deletions: one with a preserved N-terminal fragment and a marked post-SCI regenerative and recovery phenotype, and the complete Nogo-A deletion that is not associated with enhanced regeneration or recovery in mouse models of SCI. Despite the Eltrombopag Olamine inherent complexity of genetic compensation in genetic deletion studies, careful interpretation of both positive and negative data should clarify the role of Nogo-A and explain the recovery phenotypes observed in mouse, rat, and primate models of SCI[11, 26, 27, 29, 37C40]. MAG A member of the immunoglobulin superfamily, myelin associated glycoprotein (MAG), is usually a cell surface protein with five extracellular immunoglubulin-like domains, a transmembrane domain name, and two alternatively spliced C-terminal tails (Physique 1). In the CNS, MAG is usually expressed by oligodendrocytes in the periaxonal layer of myelin during.