![]() Disruption of LINGO-1 on either cell type is sufficient to overcome the inhibitory action and promote differentiation and myelination, independent of axon diameter. ![]() Whereas LINGO-1 expressed by oligodendrocytes was identified previously as an inhibitor of differentiation ( Mi et al., 2005), we demonstrate that axonal expression of LINGO-1 inhibits with equal potency. Here, we identify LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1), a molecule specific to the nervous system, as an axonal inhibitor of oligodendrocyte differentiation regulated by NGF. To identify the axonal signals regulated by NGF that control oligodendrocyte myelination, we sought out axonal signals differentially regulated by NGF that would either promote or inhibit oligodendrocyte differentiation and myelination. This was observed by the unexpected and opposite effects of NGF on SC and oligodendrocyte myelination ( Chan et al., 2004). It is quite possible that these two growth factors in the PNS share similar mechanisms promoting the expression of a common axonal signal (i.e., neuregulin-1 type III and initiate myelination).Īdditionally, recent studies concerning NGF suggest that different axonal signals control central and peripheral myelination. Similarly, nerve growth factor (NGF) acts on a different subset of nociceptive neurons expressing TrkA and is essential for myelination of these specific axons by SCs ( Chan et al., 2004). Glial cell line-derived neurotrophic factor (GDNF), a growth factor important for the development of a subset of nociceptive neurons, increases the proportion of those axons that are myelinated by SCs ( Hoke et al., 2003). In addition to neuregulin-1 type III, two other growth factors have been reported to act similarly on sensory neurons and regulate the axonal signals that promote SC myelination. Specifically, the finding that axonal neuregulin-1 type III regulates the ensheathment and thickness of the myelin sheath formed in the peripheral nervous system (PNS) by Schwann cells (SCs) has stimulated additional studies addressing how this growth factor transduces its signal and is encoded into a physiological measure of axon size ( Michailov et al., 2004 Taveggia et al., 2005). This notion has been revisited in recent years and numerous studies concerning the axonal regulation of myelination have attempted to address this particular assumption. Myelination of axons is dictated, in large part, by axonal signals that control the development of myelinating glia, and it has long been thought that axon diameter is the key determining factor for the initiation of myelination. Although some axons are myelinated and others remain unmyelinated, what are the factors that determine the expression of these signals along axons, what are these signals, and how are these signals regulated throughout development? ![]() Although the axonal factors that induce differentiation and myelination are still in question, it is well accepted that axons also control whether they will become myelinated by expressing appropriate signals to either promote or inhibit this process ( Colello and Pott, 1997). It is generally believed that during development axons will control the proliferation, survival, and differentiation of the oligodendrocyte progenitor cell (OPC). The formation of the myelin sheath is an exquisite and dynamic example of cell–cell interaction that involves the myelin-forming cell and the neuronal axon. The implications of these results relate specifically to the development of potential therapeutics targeting extrinsic growth factors that may regulate the axonal expression of modulators of oligodendrocyte development. Myelination was greatly inhibited in the presence of enforced axonal LINGO-1. Furthermore, these results were recapitulated in transgenic mice overexpressing the full length LINGO-1 under the neuronal promoter synapsin. ![]() Whereas LINGO-1 expressed by oligodendrocyte progenitor cells was previously identified as an inhibitor of differentiation, we demonstrate that axonal expression of LINGO-1 inhibits differentiation with equal potency. Here, we identify LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1) as a potent axonal inhibitor of oligodendrocyte differentiation and myelination that is regulated by nerve growth factor and its cognate receptor TrkA in a dose-dependent manner. ![]() Neurons and glia share a mutual dependence in establishing a functional relationship, and none is more evident than the process by which axons control myelination. ![]()
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