Nogo-A and Myelin-Associated Glycoprotein Mediate Neurite Growth Inhibition by Antagonistic Regulation of RhoA and Rac1

Abstract

The adult mammalian CNS has a limited capacity for nerve regeneration and structural plasticity. The presence of glia-derived inhibitory factors myelin-associated glycoprotein (MAG) and Nogo-A have been suggested to provide a nonpermissive environment for elongating nerve fibers. In particular, Nogo-A, an integral membrane protein predominantly expressed by oligodendrocytes, has been demonstrated to impair neurite growth in vitro and in vivo. Structure function analysis revealed that Nogo-A protein contains at least two active domains, NiG and Nogo-66, with diverse effects on neurite outgrowth and cell spreading. We now provide evidence that these inhibitory domains mediate their effects via an antagonistic regulation of the small GTPases RhoA and Rac1, resulting in activation of RhoA and suppression of Rac1. By inactivating RhoA with C3 transferase or the downstream effector Rho-kinase ROCK with, the inhibitory effects of both Nogo-A fragments and MAG on neurite outgrowth and oligodendrocyte-mediated growth cone collapse were abolished. Furthermore, we show that the recently cloned receptor for Nogo-66 and MAG, NgR, is not necessary for either NiG- or MAG-induced RhoA activation.

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

“…Mag is found in both the CNS and the PNS, where it is located in the periaxonal membrane, and is therefore ideally placed to interact with an axonal receptor. Mag is also found in 63 . These results show that clustering specific gangliosides in the absence of Mag and/or Ngr is sufficient to effect inhibition.…”

“…In cultured neurons, inactivation of Rho has been shown by several groups to overcome inhibition by individual inhibitors and by myelin in general 59,[61][62][63][64] . Rho has also been reported to be constitutively associated with p75 NTR , and this direct interaction causes Rho to remain active.…”

“…Another member of the Rho family of kinases, Rac, has been implicated in myelin-inhibitor signalling pathways 63 . As well as activating Rho, inhibitors in myelin inactivate Rac.…”

Nogo and Nogo‐66 receptor in human and chick: Implications for development and regeneration

“…Indeed, it has been shown recently that Nogo-A neurite growth inhibition is mediated by RhoA and RacC and does not necessarily require the presence of NgR (Niederost et al, 2002).…”

Myelin associated glycoprotein cross-linking triggers its partitioning into lipid rafts, specific signaling events and cytoskeletal rearrangements in oligodendrocytes

“…Myelin associated glycoprotein (MAG), a sialic acid-binding protein on the periaxonal myelin membrane, is implicated in the inhibition of nerve regeneration (Vyas and Schnaar, 2001;Weiss et al, 2001;Spencer et al, 2003) through its interaction with molecules on axonal plasma membranes, such as microtubule-associated protein 1B (Franzen et al, 2001), gangliosides GD1a and GT1b (Kelm et al, 1994;Crocker et al, 1996;Vinson et al, 2001;Vyas et al, 2002), and the recently discovered glycosylphosphatidylinositol (GPI)-linked Nogo receptor (neuronal receptor for Nogo, another myelin inhibitor of axonal regeneration) (Fournier et al, 2001;Domeniconi et al, 2002;Liu et al, 2002). Binding of an extracellular domain of MAG to apposing molecules on the axonal surface generates an inhibitory signal in the neuron that involves p75, RhoA and Rac1 signaling (Niederost et al, 2002;Wang et al, 2002). In addition, intracellular domains of MAG bind to microtubules (Kursula et al, 2001) and Fyn tyrosine kinase (Umemori et al, 1994;Umemori et al, 1999) in OLs.…”