Binding partners L1 cell adhesion molecule and the ezrin‐radixin‐moesin (ERM) proteins are involved in development and the regenerative response to injury of hippocampal and cortical neurons

Abstract

Regeneration of the adult central nervous system may require recapitulation of developmental events and therefore involve the re-expression of developmentally significant proteins. We have investigated whether the L1 cell adhesion molecule, and its binding partner, the ezrin-radixin-moesin (ERM) proteins are involved in the neuronal regenerative response to injury. Hippocampal and cortical neurons were cultured in vitro on either an L1 substrate or poly-L-lysine, and ERM and other neuronal proteins were localized immunocytochemically both developmentally and following neurite transection of neurons maintained in long-term culture. Activated ERM was localized to growth cones up to 7 days in vitro but relatively mature cultures (21 days in vitro) were devoid of active ERM proteins. However, ERM proteins were localized to the growth cones of sprouting neuronal processes that formed several hours after neurite transection. In addition, the L1 substrate, relative to poly-L-lysine, resulted in significantly longer regenerative neurites, as well as larger growth cones with more filopodia. Furthermore, neurons derived from the cortex formed significantly longer post-injury neurite sprouts at 6 h post-injury than hippocampal derived neurons grown on both substrates. We have demonstrated that L1 and the ERM proteins are involved in the neuronal response to injury, and that neurons derived from the hippocampus and cortex may have different post-injury regenerative neurite sprouting abilities.

L1-Mediated Branching Is Regulated by Two Ezrin-Radixin-Moesin (ERM)-Binding Sites, the RSLE Region and a Novel Juxtamembrane ERM-Binding Region

“…Previous studies have shown that ERM proteins are essential for neuronal morphogenesis and growth cone motility (Paglini et al, 1998;Castelo and Jay, 1999). In hippocampal neurons, ERM proteins were localized to growth cones and colocalized with L1 Haas et al, 2004). We have observed similar colocalization of activated ERMs and L1 in growth cones of cerebellar neurons (supplemental Fig.…”

Interaction between Telencephalin and ERM Family Proteins Mediates Dendritic Filopodia Formation

“…A functional binding between L1, an axonal adhesion molecule belonging to the Ig superfamily, and ERM proteins is involved in neurite branching during development and regenerative response to injury (Dickson et al, 2002;Haas et al, 2004;Cheng et al, 2005). In axonal growth cones, radixin and moesin regulate their morphology and motility (Paglini et al, 1998;Castelo and Jay, 1999).…”

Growth-associated protein GAP-43 and L1 act synergistically to promote regenerative growth of Purkinje cell axons in vivo

“…Dunican and Doherty (36) suggest that when N-CAM, L1, or N-cadherin on a growth cone binds a suitable ligand, clustering and activation of FGF receptors leads to phosphorylation of GAP-43 and, as a result, to neurite outgrowth-promoting changes in the actin cytoskeleton. Thus, although the neurite growth-promoting effect of CAMs may be mediated by multiple intracellular signal transduction pathways (16,37,40), the Dunican and Doherty model would explain why coexpression of L1 and GAP-43 by neurons is associated with greater axon sprouting than occurs with the expression of either L1 or GAP-43 alone.…”

“…Its effects are mediated by homophilic binding to L1 or heterophilic binding to ligands, including integrins, on other cells, or by binding to extracellular matrix-associated molecules, including chondroitin sulfate proteoglycans, neurocan, and phosphacan (15). The intracellular domain of L1 binds to ezrin-radixinmoesin membrane-cytoskeleton linker proteins that are involved in growth cone morphology and motility and second messenger pathways (16,17). L1 also interacts with FGF receptors, and L1-induced neurite outgrowth requires the tyrosine kinase activity of FGF receptors to activate intracellular signaling cascades, including Ras͞mitogen-activated protein kinase and phospholipase-C␥͞diacyl-glycerol͞Ca 2ϩ ͞PKC pathways (15,18,19).…”