Two PTP receptors mediate CSPG inhibition by convergent and divergent signaling pathways in neurons

Abstract

Receptor protein tyrosine phosphatase σ (PTPσ) and its subfamily member LAR act as transmembrane receptors that mediate growth inhibition of chondroitin sulfate proteoglycans (CSPGs). Inhibition of either receptor increases axon growth into and beyond scar tissues after CNS injury. However, it is unclear why neurons express two similar CSPG receptors, nor whether they use the same or different intracellular pathways. We have now studied the signaling pathways of these two receptors using N2A cells and primary neurons derived from knockout mice. We demonstrate that both receptors share certain signaling pathways (RhoA, Akt and Erk), but also use distinct signals to mediate CSPG actions. Activation of PTPσ by CSPGs selectively inactivated CRMP2, APC, S6 kinase and CREB. By contrast LAR activation inactivated PKCζ, cofilin and LKB1. For the first time, we propose a model of the signaling pathways downstream of these two CSPG receptors. We also demonstrate that deleting both receptors exhibits additive enhancement of axon growth in adult neuronal cultures in vitro. Our findings elucidate the novel downstream pathways of CSPGs and suggest potential synergy of blocking their two PTP receptors.

Chondroitin sulfate proteoglycans negatively regulate the positioning of mitochondria and endoplasmic reticulum to distal axons

“…(E)]. CSPGs also decrease Erk signaling (Ohtake et al, ). However, inhibition of Mek‐Erk signaling using PD325901 (1 μ M , 1 h) also did not affect either Mito‐Tip ( p = 0.75, n = 166 and 144) or the number of mitochondria in growth cones ( p = 0.97) on the control substratum.…”

“…The LAR receptor inhibits PI3K and Erk signaling and activates RhoA‐ROCK (Fisher et al, ; Ohtake et al, ) and is localized to the growth cones of the chicken sensory neurons used in this study (Ketschek et al, ). The data indicate a sufficient and necessary role for suppression of PI3K signaling, but not ROCK or Erk, downstream of LAR in the effects of CSPGs on mitochondria positioning at growth cones.…”

“…The LAR and PTPσ receptors mediate most inhibitory effects of CSPGs (Sharma et al, ). Binding of CSPGs to either receptor decreases PI3K signaling and activates RhoA‐ROCK signaling (Fisher et al, ; Silver et al, ; Ohtake et al, ), and both restoration of PI3K signaling and inhibition of ROCK signaling partially counter the effects of CSPGs on axon extension (Monnier et al, ; Jain et al, ; Silver et al, ). CSPGs also attenuate Erk signaling in neurons (Ohtake et al, ).…”

LAR and PTPσ receptors are negative regulators of oligodendrogenesis and oligodendrocyte integrity in spinal cord injury

“…In NPCs, we found that ROCK inhibition allows NPCs to grow on CSPGs and promote their survival and oligodendrogenesis (Dyck et al, ). Similarly, genetic knockdown approaches have implicated both LAR and PTPσ in mediating Rho activation in primary cerebellar granule neurons (Ohtake, Wong, Abdul‐Muneer, Selzer, & Li, ). Notably, Rho activation has been associated with p75‐mediated apoptosis in neurons and glial cells (Dubreuil et al, ); however, its link to LAR and PTPσ has not been reported previously.…”

“…In NPCs, we found that ROCK inhibition allows NPCs to grow on CSPGs and promote their survival and oligodendrogenesis . Similarly, genetic knockdown approaches have implicated both LAR and PTPσ in mediating Rho activation in primary cerebellar granule neurons (Ohtake, Wong, Abdul-Muneer, Selzer, & Li, 2016).…”