Nogo Domains and a Nogo Receptor:Implications for Axon Regeneration

Abstract

and Program in Neuroscience show that failure to regenerate is not purely an intrinsic Harvard Medical School deficit of CNS neurons, and is blocked by the CNS envi-Boston, Massachusetts 02115 ronment. Two main sites have been considered for the location Diagnosis: You should say of him: "One having a crushed of CNS factors that might inhibit axon regeneration (Figvertebra in his neck; he is unconscious of his two arms, ure 1). One site is the scar that forms at the region of his two legs, he is speechless. An ailment not to be injury. Following CNS injury the central area of necrosis treated." is infiltrated by glia and other nonneuronal cells, and a -Edwin Smith Surgical Papyrus, c. 2500-1600 B.C. fibrous scar forms. Axons do not extend through the scar and appear to be inhibited by it, with the axon tips forming club-like structures that can remain in place for Unfortunately, little has changed clinically in the several months or even years. Molecular components that may thousand years since this anonymous author gave us contribute to this inhibitory activity include chondroitin the first known descriptions of the tragic consequences sulfate proteoglycans (CSPG), tenascin, and semaphoof central nervous system (CNS) injury, and the limited rin-3A, which are upregulated in the region of scarring therapeutic options (Breasted, 1930). Today, it is estiand are inhibitory to axon growth in culture (Letourneau mated that more than 250,000 Americans have spinal et al., 1994; Davies et al., 1999; Pasterkamp et al., 1999, cord injuries, with 11,000 new cases every year (Berkoand references therein). Moreover, glial scar tissue witz et al., 1998). When axonal connections are damaged placed in culture can be converted to a permissive subin the adult brain or spinal cord, they show an extremely strate by enzymatic removal of glycosaminoglycans, limited ability to regenerate, even though axons can supporting the idea that CSPG is an important compogrow and regenerate efficiently in the embryonic CNS, nent. It is worth bearing in mind that proteoglycans bind and in the adult peripheral nervous system. What are many other molecules, and their role could be as a scafthe reasons for this selective shutdown of regeneration fold that presents molecular cues to the responding cell. in the adult CNS? Factors that may play a role can be The other main proposal is that inhibitors would be grouped in two categories: intrinsic properties of CNS broadly distributed in the myelin that ensheaths axons neurons that may make them incapable of regenerating, in white matter tracts of the adult CNS. Supporting this or extrinsic factors in the environment that may influence idea, the loss of regeneration potential during developaxon growth positively or negatively (reviewed by Horner ment correlates roughly with the onset of myelination. and Gage, 2000). Here, we focus on extrinsic negative Moreover, myelin carpets or oligodendrocytes, the cells factors, particularly recent studies of the inhibitory molethat produce CNS myelin, are poor substra...

Myelin‐, reactive glia‐, and scar‐derived CNS axon growth inhibitors: Expression, receptor signaling, and correlation with axon regeneration

“…lipid rafts with another transmembrane signal-transducing polypeptide (Brittis and Flanagan, 2001), now known to be p75 NTR . The transmembrane Rc p75 NTR (Fig.…”

Repulsive Guidance Molecule (RGM) Gene Function Is Required for Neural Tube Closure But Not Retinal Topography in the Mouse Visual System

“…For example, only small amounts of NogoA protein reach the cell surface of oligodendrocytes and the most prominent localization of NogoA is found in the endoplasmic reticulum (Chen et al, 2000;GrandPre et al, 2000). It has been suggested that NogoA protein may be released from oligodendrocytes only after lesion of the nervous system, thus preventing NogoA from acting under normal circumstances (Brittis and Flanagan, 2001). Moreover, Commissureless in Drosophila has recently been described to sort Roundabout, the receptor for the repulsive guidance molecule Slit, to the endosomal compartment to prevent commissural neurons from responding to Slit before midline crossing (Keleman et al, 2002).…”

Nogo enhances the adhesion of olfactory ensheathing cells and inhibits their migration

“…Nogo is a member of the reticulon family and occurs in three forms, Nogo-A, Nogo-B and Nogo-C, which are generated from alternate splicing (GrandPre et al, 2000). All three isoforms of Nogo share a 66-amino-acid-residue luminal/extracellular domain (Nogo-66), which inhibits axonal extension and fibroblast spreading (Brittis and Flanagan, 2001;Fournier et al, 2001). The molecular cloning of Nogo (Chen et al, 2000;GrandPre et al, 2000;Prinjha et al, 2000) led to the identification of a neuronal surface glycosyl phosphatidylinositol (GPI)-linked receptor that binds with high affinity to Nogo-66, termed the Nogo-66 receptor (NgR) (Fournier et al, 2001).…”