The molecular mechanisms of Nogo signaling

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The molecular mechanisms of  Nogo signaling

Summary    3
Inhibition of axon regeneration in the CNS    4
Astrocytes and the glial scar    4
Myelin associated inhibitors    4
Nogo, the principal myelin associated inhibitor    5
Nogo is a member of the RTN protein family    6
Nogo structure    6
The stucture of the Nogo RTN domain    6
Nogo-A and B specific domains    7
Membrane topology    7
Nogo receptors    8
Downstream signaling in the CNS    9
Activation of RhoA, the second messenger for cytoskeletal dynamics    9
The RhoA-ROCK pathway and its downstream effectors    10
Activation of Ca2+ and cAMP signaling pathways    11
Signal transduction downstream of Ca2+ and cAMP mediates a switch in axonal response    12
Downstream effectors of cAMP influence neurite outgrowth    12
cAMP levels control regenerative capacity after a preconditioning lesion and during maturation    13
Nogo functions in the nervous system    13
Nogo-A hampers axonal regeneration after CNS injury    13
Roles of Nogo in the developing CNS    14
Nogo regulates plasticity of the adult CNS    15
Nogo-B and C in myelin associated inhibition    15
Specific functions of Nogo-B and C    15
Discussion    17
List of Abbreviations    18
Refrences    19

Summary

Damage to the adult central nervous system often leads to permanent loss of function. Several inhibitory factors specific for the CNS prevent regeneration of severed axons and network connectivity is lost permanently. One obstacle for regenerating neurons is formed by myelin associated inhibitors; the proteins Nogo, MAG and OMgp, which are expressed by myelinating oligodendrocytes in the CNS. Of these three, Nogo is believed to be the main mediator of growth inhibition in the adult CNS. The nogo gene gives rise to three protein products, the Nogo isoforms A, B and C. Nogo-A the isoform that functions as an inhibitor for neuronal growth, during development Nogo-A is involved in axonal guidance and in the uninjured adult CNS Nogo regulates functional plasticity. Nogo-B and C are less well studied jet some specific functions are known. Signaling by Nogo-A involves multiple receptors that activate parallel cascades of downstream effectors. These signaling pathways ultimately lead to a halt in axon growth. Signaling commences when Nogo binds to one of its receptors. To date, two receptors for Nogo-A have been identified, NgR1 and co-receptors LINGO-1 and p75 or TROY, and the receptor PirB. Via these receptors, multiple signaling routes involving RhoA, cAMP and Ca²⁺ are activated. These second messengers and their downstream effectors determine growth direction and induce growth cone collapse. In vitro studies of Nogo function confirm its role as an inhibitor of neuronal growth and regeneration. However, in vivo studies of Nogo function in animals lacking one or more Nogo isoforms show inconsistent regeneration phenotypes. In contrast, treatment with function blocking anti-Nogo antibodies has profound and consistent positive effects on regeneration of the CNS and recovery of motor function. These Nogo blocking antibodies have great therapeutic potential and are currently being evaluated in clinical trials. The antibodies may soon be available to patients with CNS injuries and greatly improve their rehabilitation.

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