Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibi...Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.展开更多
Nogo-A is a major myelin associated inhibitor that blocks regeneration of injured axons in the central nervous system （CNS）. Nogo-66 （a 66-residue domain of Nogo-A） expressed on the surface of oligodendrocytes has...Nogo-A is a major myelin associated inhibitor that blocks regeneration of injured axons in the central nervous system （CNS）. Nogo-66 （a 66-residue domain of Nogo-A） expressed on the surface of oligodendrocytes has been shown to directly interact with Nogo-66 receptor 1 （NgRI）. A number of additional components of NgR1 receptor complex essential for its signaling have been uncovered. However, detailed composition of the complex and its signaling mechanisms remain to be fully elucidated. In this study, we show that Nogo receptor 3 （NgR3）, a paralog of NgRI, is a binding protein for NgR1. The interaction is highly specific because other members of the reticulin family, to which Nogo-A belongs, do not bind to NgR3. Neither does NgR3 show any binding activity with Nogo receptor 2 （NgR2）, another NgRI paralog. Majority of NgR3 domains are required for its binding to NgR1. Moreover, a truncated NgR3 with the membrane anchoring domain deleted can function as a decoy receptor to reverse neurite outgrowth inhibition caused by Nogo-66 in culture. These in vitro results, together with previously reported overlapping expression profile between NgR1 and NgR3, suggest that NgR3 may be associated with NgR1 in vivo and that their binding interface may be targeted for treating neuronal injuries.展开更多
基金a Ph D fellowship by FCT-Fundacao para a Ciência Tecnologia (SFRH/BD/135868/2018)(to SSC)。
文摘Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.
基金supported by Ministry of Science and Technology(2007CB947201)Chinese Academy of Sciences (XDA01010108)National Science Foundation of China (30425013)to J.Z.
文摘Nogo-A is a major myelin associated inhibitor that blocks regeneration of injured axons in the central nervous system （CNS）. Nogo-66 （a 66-residue domain of Nogo-A） expressed on the surface of oligodendrocytes has been shown to directly interact with Nogo-66 receptor 1 （NgRI）. A number of additional components of NgR1 receptor complex essential for its signaling have been uncovered. However, detailed composition of the complex and its signaling mechanisms remain to be fully elucidated. In this study, we show that Nogo receptor 3 （NgR3）, a paralog of NgRI, is a binding protein for NgR1. The interaction is highly specific because other members of the reticulin family, to which Nogo-A belongs, do not bind to NgR3. Neither does NgR3 show any binding activity with Nogo receptor 2 （NgR2）, another NgRI paralog. Majority of NgR3 domains are required for its binding to NgR1. Moreover, a truncated NgR3 with the membrane anchoring domain deleted can function as a decoy receptor to reverse neurite outgrowth inhibition caused by Nogo-66 in culture. These in vitro results, together with previously reported overlapping expression profile between NgR1 and NgR3, suggest that NgR3 may be associated with NgR1 in vivo and that their binding interface may be targeted for treating neuronal injuries.
