Neurotrophin Binding to the p75 Receptor Modulates Rho Activity and Axonal Outgrowth

Abstract

While the neurotrophin receptor p75NTR is expressed by many developing neurons, its function in cells escaping elimination by programmed cell death remains unclear. The lack of intrinsic enzymatic activity of p75NTR prompted a search for protein interactors expressed in the developing retina, which resulted in the identification of the GTPase RhoA. In transfected cells, p75NTR activated RhoA, and neurotrophin binding abolished RhoA activation. In cultured neurons, inactivation of Rho proteins mimicked the effect of neurotrophins by increasing the rate of neurite elongation. In vivo, axonal outgrowth was retarded in mice carrying a mutation in the p75NTR gene. These results indicate that p75NTR modulates in a ligand-dependent fashion the activity of intracellular proteins known to regulate actin assembly.

Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants

“…These studies further validate Rho signaling as an important element in the attenuation of anti-cancer drug induced neurotoxicity. Since Rho GTPases are now well established as a convergence point downstream of p75 NTR in the regulation of neurite outgrowth (Domeniconi et al, 2005;Yamashita and Tohyama, 2003;Yamashita et al, 1999;Yamauchi et al, 2004), we propose that the inhibition of p75 NTR activation of Rho GTPases is important to maintain normal neuronal morphology during anti-cancer drug exposure.…”

“…Ligand activation of p75 NTR neurotrophin receptor is known to suppress Rho GTPase activity (Yamashita et al, 1999). LM11A-31 is a recently described small molecule ligand of p75 NTR that induces survival signaling and inhibits proNGF-induced neuronal death (Massa et al, 2003;Massa et al, 2006).…”

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

“…57 Ligand-bound NgR associates with p75 and LINGO-1 to activate the GTPase RhoA, which transduces myelin-derived inhibition to the cytoskeleton. [58][59][60] Since p75 binds neurotrophins, its contribution to axonal growth is complex (see below), whereas the activation of RhoA leads to the recruitment of Rho kinase and subsequent remodeling of the actin cytoskeleton to inhibit regeneration. Targeting the Rho pathway with the bacterial enzyme C3 transferase or with specific inhibitors of Rho kinase has led to reports of both corticospinal regeneration and functional recovery after rat SCI.…”

“…With the addition of ligand (such as NGF), RhoA activation is inhibited, promoting growth cone motility and neurite outgrowth. 58 On the other hand, several studies have pointed to a negative role of p75 in neurotrophin signaling and neurite outgrowth: activating p75 in PC-12 cells with BDNF inhibited trkA activation through the ceramide pathway; 170 in sensory neuronal compartmented cultures, binding of BDNF or a p75-specific antibody inhibited NGF-mediated trkA phosphorylation and slowed neurite outgrowth; 171 and in vitro and in vivo, BDNF-mediated p75 activation inhibited sympathetic neurite outgrowth and target innervation. 172 Additionally, in p75 À/À mice in vivo, some brain structures are normally hyperinnervated, 173 and regeneration following peripheral nerve injury is more robust in p75 knockouts than in wild-type mice.…”

“…178 More recently, it has been suggested that p75 mediates inhibitory signaling of myelin-derived inhibitory proteins (see above). [58][59][60] Upon binding to the common receptor for these proteins (the Nogo receptor), p75 is activated, leading to RhoA activation and inhibition of actin polymerization at the growth cone. On balance, these findings indicate a clear rationale for blocking p75 function in order to extend neurotrophinmediated regeneration into or within the CNS following injury.…”