Neurotrophins support regenerative axon assembly over CSPGs by an ECM-integrin-independent mechanism

Abstract

Chondroitin sulfate proteoglycans (CSPGs) and myelin-based inhibitors are the most studied inhibitory molecules in the adult central nervous system. Unlike myelin-based inhibitors, few studies have reported ways to overcome the inhibitory effect of CSPGs. Here, by using regenerating adult dorsal root ganglion (DRG) neurons, we show that chondroitin sulfate proteoglycans inhibit axon assembly by a different mechanism from myelin-based inhibitors. Furthermore, we show that neither Rho inhibition nor cAMP elevation rescues extracellular factor-induced axon assembly inhibited by CSPGs. Instead, our data suggest that CSPGs block axon assembly by interfering with integrin signaling. Surprisingly, we find that nerve growth factor (NGF) promotes robust axon growth of regenerating DRG neurons over CSPGs. We have found that, unlike naive neurons that require simultaneous activation of neurotrophin and integrin pathways for axon assembly, either neurotrophin or integrin signaling alone is sufficient to induce axon assembly of regenerating neurons. Thus, our results suggest that the ability of NGF to overcome CSPG inhibition in regenerating neurons is probably due to the ability of regenerating neurons to assemble axons using an integrin-independent pathway. Finally, our data show that the GSK-3β-APC pathway, previously shown to mediate developing axon growth, is also necessary for axon regeneration.

MicroRNA-138 and SIRT1 form a mutual negative feedback loop to regulate mammalian axon regeneration

“…We next studied the role of miR-138 in the regulation of axon regeneration using adult sensory neurons from the dorsal root ganglion (DRG), which regenerate robustly after peripheral nerve injury by reactivating their intrinsic axon regeneration capacity (Zhou et al 2006). Similarly, we first examined the expression level of endogenous miR-138 in adult DRG neurons during peripheral axotomy-induced axon regeneration using qRT-PCR.…”

Schwann cell migration is integrin‐dependent and inhibited by astrocyte‐produced aggrecan

“…In view of the preceding data and published data showing that proteoglycans can disrupt integrin function and signaling (McKeon et al, 1995;Zhou et al, 2006), we examined whether aggrecan can affect integrin function in Schwann cells. The key event that links the binding of activated integrins to ligands and their effects on cell behavior is the activation of focal adhesion kinase (FAK) by phosphorylation.…”

“…In the undamaged postnatal CNS, aggrecan is present as a component of perineuronal nets, structures around neurons responsible for restricting the plasticity of the adult nervous system (Carulli et al, 2006;Lemons et al, 2001), and is produced by both neurons and astrocytes (Asher et al, 1995;Carulli et al, 2006;Hernandez et al, 2002). The mechanism by which CSPGs such as aggrecan mediate their inhibitory effect is not understood although studies have suggested that they can disrupt integrin function (McKeon et al, 1995;Zhou et al, 2006). In this study we provide evidence that astrocyte-produced aggrecan inhibits Schwann cell migration, and that this inhibition involves modulation of Schwann cell integrin function.…”

The effects of erythropoietin on RhoA/Rho-associated kinase expression in rat retinal explants cultured with glutamate

“…A number of studies have confirmed that Rho and its associated signaling molecules are involved in and mediate the biological processes of axon regeneration, extension and fiber projection (28)(29)(30)(31). Rho regulates the cell actin cytoskeleton by its downstream effective factor ROCK, which is extensively involved in the biological processes of cell migration, movement, apoptosis, gene transcription and nerve regeneration (32).…”