The intrinsic growth ability of all the neurons declines during development although some may grow better than others. Numerous intracellular signaling proteins and transcription factors have been shown to regulate th...The intrinsic growth ability of all the neurons declines during development although some may grow better than others. Numerous intracellular signaling proteins and transcription factors have been shown to regulate the intrinsic growth capacity in mature neurons. Among them, PI3 kinase/Akt pathway is important for controlling axon elongation. As a negative regulator of this pathway, the tumor suppressor phosphatase and tensin homolog （PTEN） appears critical to con- trol the regenerative ability of young and adult neurons. This review will focus on recent research progress in axon regeneration and neural repair by PTEN inhibition and therapeutic potential of blocking this phosphatase for neurological disorders. Inhibition of PTEN by deletion in con- ditional knockout mice, knockdown by short-hairpin RNA, or blockade by pharmacological approaches, including administration of selective PTEN antagonist peptides, stimulates various degrees of axon regrowth in juvenile or adult rodents with central nervous system injuries. Im- portantly, post-injury PTEN suppression could enhance axonal growth and functional recovery in adult central nervous system after injury.展开更多
Several major factors are known to contribute to CNS axon regenerative failure after injury, including reduced intrinsic growth capacity of developed neurons and extrinsic factors mediating axon outgrowth. For the lat...Several major factors are known to contribute to CNS axon regenerative failure after injury, including reduced intrinsic growth capacity of developed neurons and extrinsic factors mediating axon outgrowth. For the latter, a non-permissive environment around the lesion and the lack of sufficient neurotrophic support within the adult CNS play important roles （Silver et al., 2015）. In addition to generation of various inhibitory substrates by oligodendrocytes, fibrotic tissues, inflammatory cells and other cell types, reactive astrocytes surrounding lesions are thought to highly suppress regeneration of injured CNS axons （Silver and Miller, 2004; Ohtake and Li, 2014）. A great number of studies suggest that reactive astrocytic scars form one of the major barriers preventing axon regeneration after CNS iniuries, including spinal cord injury （SCI）. However, reactive astrocytes were reported to provide a beneficial role by reducing infiltrating immunoreactive cells into adjacent domains, protecting bordering neural tissue from damage and generating numerous supportive extracellular matrix （ECM） components to promote cell survival and growth （Bush et al., 1999）. Previ- ous data showed that ablation of reactive astrocytes increased inflammation and secondary tissue damage, prevented blood- brain barrier formation and increased local neurite growth. Interestingly, a recent study by Anderson et al （2016） provides evidence that reactive astrocytes around the lesioned spinal cord support axon regeneration after SCI, rather than block regrowth （Anderson et al., 2016）.展开更多
基金supported by research grants to SL from NIH(1R21NS066114,1R01NS079432 and 1R01EY024575)Christopher&Dana Reeve Foundation(LA1-1002-2)Shriners Research Foundation(86300)
文摘The intrinsic growth ability of all the neurons declines during development although some may grow better than others. Numerous intracellular signaling proteins and transcription factors have been shown to regulate the intrinsic growth capacity in mature neurons. Among them, PI3 kinase/Akt pathway is important for controlling axon elongation. As a negative regulator of this pathway, the tumor suppressor phosphatase and tensin homolog （PTEN） appears critical to con- trol the regenerative ability of young and adult neurons. This review will focus on recent research progress in axon regeneration and neural repair by PTEN inhibition and therapeutic potential of blocking this phosphatase for neurological disorders. Inhibition of PTEN by deletion in con- ditional knockout mice, knockdown by short-hairpin RNA, or blockade by pharmacological approaches, including administration of selective PTEN antagonist peptides, stimulates various degrees of axon regrowth in juvenile or adult rodents with central nervous system injuries. Im- portantly, post-injury PTEN suppression could enhance axonal growth and functional recovery in adult central nervous system after injury.
文摘Several major factors are known to contribute to CNS axon regenerative failure after injury, including reduced intrinsic growth capacity of developed neurons and extrinsic factors mediating axon outgrowth. For the latter, a non-permissive environment around the lesion and the lack of sufficient neurotrophic support within the adult CNS play important roles （Silver et al., 2015）. In addition to generation of various inhibitory substrates by oligodendrocytes, fibrotic tissues, inflammatory cells and other cell types, reactive astrocytes surrounding lesions are thought to highly suppress regeneration of injured CNS axons （Silver and Miller, 2004; Ohtake and Li, 2014）. A great number of studies suggest that reactive astrocytic scars form one of the major barriers preventing axon regeneration after CNS iniuries, including spinal cord injury （SCI）. However, reactive astrocytes were reported to provide a beneficial role by reducing infiltrating immunoreactive cells into adjacent domains, protecting bordering neural tissue from damage and generating numerous supportive extracellular matrix （ECM） components to promote cell survival and growth （Bush et al., 1999）. Previ- ous data showed that ablation of reactive astrocytes increased inflammation and secondary tissue damage, prevented blood- brain barrier formation and increased local neurite growth. Interestingly, a recent study by Anderson et al （2016） provides evidence that reactive astrocytes around the lesioned spinal cord support axon regeneration after SCI, rather than block regrowth （Anderson et al., 2016）.
