Protein kinase C mediates neurite guidance at an astrocyte boundary

Powell, Elizabeth M.; Mercado, Mary Lynn T.; Calle, Yolanda; Geller, Herbert M.

doi:10.1002/1098-1136(20010315)33:4<288::aid-glia1027>3.0.co;2-r

Cited by 34 publications

(26 citation statements)

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“…2) (Dill et al, 2008; Fu et al, 2007; Monnier et al, 2003; Powell et al, 2001; Sivasankaran et al, 2004). PTPσ and LAR bind CSPG with high affinity as the CSPG receptors (Fisher et al, 2011; Shen et al, 2009), but their downstream signaling pathways to mediate neuron growth failure are less clear.…”

Section: Downstream Signaling Pathways That Convey Growth Inhibitimentioning

confidence: 99%

Molecular mechanisms of scar-sourced axon growth inhibitors

Ohtake

2015

Brain Research

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Astrogliosis is a defense response of the CNS to minimize primary damage and to repair injured tissues, but it ultimately generates harmful effects by upregulating inhibitory molecules to suppress neuronal elongation and forming potent barriers to axon regeneration. Chondroitin sulfate proteoglycans (CSPGs) are highly expressed by reactive scars and are potent contributors to the non-permissive environment in mature CNS. Surmounting strong inhibition by CSPG-rich scar is an important therapeutic goal for achieving functional recovery after CNS injuries. Currently, enzymatic digestion of CSPGs with locally applied chondroitinase ABC is the main in vivo approach to overcome scar inhibition, but several disadvantages may prevent using this bacterial enzyme as a therapeutic option for patients. A better understanding of molecular mechanisms underlying CSPG function may facilitate development of new effective therapies to overcome scar-mediated inhibition. Previous studies support that CSPGs act by non-specifically hindering the binding of matrix molecules to their cell surface receptors through steric interactions, but two members of the leukocyte common antigen related (LAR) phosphatase subfamily, protein tyrosine phosphatase σ and LAR, are functional receptors that bind CSPGs with high affinity and mediate CSPG inhibition. CSPGs may also act by binding two receptors for myelin-associated growth inhibitors, Nogo receptors 1 and 3. Thus, CSPGs inhibit axon growth through multiple mechanisms, making them especially potent and difficult therapeutic targets. Identification of CSPG receptors is not only important for understanding the scar-mediated growth suppression, but also for developing novel and selective therapies to promote axon sprouting and/or regeneration after CNS injuries.

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Section: Downstream Signaling Pathways That Convey Growth Inhibitimentioning

confidence: 99%

Molecular mechanisms of scar-sourced axon growth inhibitors

Ohtake

2015

Brain Research

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“…Several intracellular signals have been reported to mediate CSPG inhibition on neuronal growth, including Akt/PKB (protein kinase B), glycogen synthase kinase 3β (GSK-3β), RhoA, protein kinase C and others (Dill et al 2008; Fu et al 2007; Monnier et al 2003; Powell et al 2001; Sivasankaran et al 2004). We recently determined the downstream signaling pathways that mediate CSPG-LAR interactions by measuring activities of Akt, RhoA and CRMP2 in cerebellar granule neurons derived from postnatal LAR −/− or +/+ mice.…”

Section: Downstream Signaling Pathways To Convey Growth Inhibition Bymentioning

confidence: 99%

Scar-mediated inhibition and CSPG receptors in the CNS

Sharma

Selzer

2012

Experimental Neurology

160

128

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Severed axons in adult mammals do not regenerate appreciably after central nervous system (CNS) injury due to developmentally determined reductions in neuron-intrinsic growth capacity and extracellular environment for axon elongation. Chondroitin sulfate proteoglycans (CSPGs), which are generated by reactive scar tissues, are particularly potent contributors to the growth-limiting environment in mature CNS. Thus, surmounting the strong inhibition by CSPG-rich scar is an important therapeutic goal for achieving functional recovery after CNS injuries. As of now, the main in vivo approach to overcoming inhibition by CSPGs is enzymatic digestion with locally applied chondroitinase ABC (ChABC), but several disadvantages may prevent using this bacterial enzyme as a therapeutic option for patients. A better understanding of the molecular mechanisms underlying CSPG action is needed in order to develop more effective therapies to overcome CSPG-mediated inhibition of axon regeneration and/or sprouting. Because of their large size and dense negative charges, CSPGs were thought to act by non-specifically hindering the binding of matrix molecules to their cell surface receptors through steric interactions. Although this may be true, recent studies indicate that two members of the leukocyte common antigen related (LAR) phosphatase subfamily, protein tyrosine phosphatase σ (PTPσ) and LAR, are functional receptors that bind CSPGs with high affinity and mediate CSPG inhibitory effects. CSPGs also may act by binding to two receptors for myelin-associated growth inhibitors, Nogo receptors 1 and 3 (NgR1 and NgR3). If confirmed, it would suggest that CSPGs have multiple mechanisms by which they inhibit axon growth, making them especially potent and difficult therapeutic targets. Identification of CSPG receptors is not only important for understanding the scar-mediated growth suppression, but also for developing novel and selective therapies to promote axon sprouting and/or regeneration after CNS injuries, including spinal cord injury (SCI).

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“…PKC can mediate neurite guidance at the astrocyte boundary in coculture of neurons and astrocytes (Powell et al, 2001) and participate in the midline axon guidance in mice through its phosphorylation of GAP-43 (Zhang et al, 2000;Shen et al, 2002). A gradient of PKC activator has been reported to produce a significant growth cone attraction (Fu et al, 1997).…”

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confidence: 99%