Axonal degeneration is a key pathological feature in many neurological diseases. It often leads to persistent deficits due to the inability of axons to regenerate in the central nervous system. Therefore therapeutic a...Axonal degeneration is a key pathological feature in many neurological diseases. It often leads to persistent deficits due to the inability of axons to regenerate in the central nervous system. Therefore therapeutic approaches should optimally both attenuate axonal degeneration and foster axonal regeneration. Compelling evidence suggests that collapsin response mediator protein-2（CRMP2） might be a molecular target fulfilling these requirements. In this mini-review, we give a compact overview of the known functions of CRMP2 and its molecular interactors in neurite outgrowth and in neurodegenerative conditions. Moreover, we discuss in detail our recent findings on the role of CRMP2 in acute axonal degeneration in the optic nerve. We found that the calcium influx induced by the lesion activates the protease calpain which cleaves CRMP2, leading to impairment of axonal transport. Both calpain inhibition and CRMP2 overexpression effectively protected the proximal axons against acute axonal degeneration. Taken together, CRMP2 is further characterized as a central molecular player in acute axonal degeneration and thus evolves as a promising therapeutic target to both counteract axonal degeneration and foster axonal regeneration in neurodegenerative and neurotraumatic diseases.展开更多
Recent studies have shown that mutation at Ser522 causes inhibition of collapsin response mediator protein 2(CRMP2) phosphorylation and induces axon elongation and partial recovery of the lost sensorimotor function af...Recent studies have shown that mutation at Ser522 causes inhibition of collapsin response mediator protein 2(CRMP2) phosphorylation and induces axon elongation and partial recovery of the lost sensorimotor function after spinal cord injury(SCI).We aimed to reveal the intracellular mechanism in axotomized neurons in the CRMP2 knock-in(CRMP2KI) mouse model by performing transcriptome analysis in mouse sensorimotor cortex using micro-dissection punching system.Prior to that, we analyzed the structural pathophysiology in axotomized or neighboring neurons after SCI and found that somatic atrophy and dendritic spine reduction in sensorimotor cortex were suppressed in CRMP2KI mice.Further analysis of the transcriptome has aided in the identification of four hemoglobin genes Hba-a1, Hba-a2, Hbb-bs, and Hbb-bt that are significantly upregulated in wild-type mice with concomitant upregulation of genes involved in the oxidative phosphorylation and ribosomal pathways after SCI.However, we observed substantial upregulation in channel activity genes and downregulation of genes regulating vesicles, synaptic function, glial cell differentiation in CRMP2KI mice.Moreover, the transcriptome profile of CRMP2KI mice has been discussed wherein energy metabolism and neuronal pathways were found to be differentially regulated.Our results showed that CRMP2KI mice displayed improved SCI pathophysiology not only via microtubule stabilization in neurons, but also possibly via the whole metabolic system in the central nervous system, response changes in glial cells, and synapses.Taken together, we reveal new insights on SCI pathophysiology and the regenerative mechanism of central nervous system by the inhibition of CRMP2 phosphorylation at Ser522.All these experiments were performed in accordance with the guidelines of the Institutional Animal Care and Use Committee at Waseda University, Japan(2017-A027 approved on March 21, 2017;2018-A003 approved on March 25, 2018;2019-A026 approved on March 25, 2019).展开更多
Neurogenesis is the process in which neurons are generated from neural stem/progenitor cells(NSCs/NPCs).It involves the proliferation and neuronal fate specification/differentiation of NSCs,as well as migration,maturat...Neurogenesis is the process in which neurons are generated from neural stem/progenitor cells(NSCs/NPCs).It involves the proliferation and neuronal fate specification/differentiation of NSCs,as well as migration,maturation and functional integration of the neuronal progeny into neuronal network.NSCs exhibit the two essential properties of stem cells:self-renewal and multi-potency.Contrary to previous dogma that neurogenesis happens only during development,it is generally accepted now that neurogenesis can take place throughout life in mammalian brains.This raises a new therapeutic potential of applying stem cell therapy for stroke,neurodegenerative diseases and other diseases.However,the maintenance and differentiation of NSCs/NPCs are tightly controlled by the extremely intricate molecular networks.Uncovering the underlying mechanisms that drive the differentiation,migration and maturation of specific neuronal lineages for use in regenerative medicine is,therefore,crucial for the application of stem cell for clinical therapy as well as for providing insight into the mechanisms of human neurogenesis.Here,we focus on the role of bone morphogenetic protein(BMP)signaling in NSCs during mammalian brain development.展开更多
文摘Axonal degeneration is a key pathological feature in many neurological diseases. It often leads to persistent deficits due to the inability of axons to regenerate in the central nervous system. Therefore therapeutic approaches should optimally both attenuate axonal degeneration and foster axonal regeneration. Compelling evidence suggests that collapsin response mediator protein-2（CRMP2） might be a molecular target fulfilling these requirements. In this mini-review, we give a compact overview of the known functions of CRMP2 and its molecular interactors in neurite outgrowth and in neurodegenerative conditions. Moreover, we discuss in detail our recent findings on the role of CRMP2 in acute axonal degeneration in the optic nerve. We found that the calcium influx induced by the lesion activates the protease calpain which cleaves CRMP2, leading to impairment of axonal transport. Both calpain inhibition and CRMP2 overexpression effectively protected the proximal axons against acute axonal degeneration. Taken together, CRMP2 is further characterized as a central molecular player in acute axonal degeneration and thus evolves as a promising therapeutic target to both counteract axonal degeneration and foster axonal regeneration in neurodegenerative and neurotraumatic diseases.
基金supported by Grants-in-Aid for Scientific Research on Priority Areas from The Ministry of Education, Culture, Sports, Science and Technology(No.26430043to TO)。
文摘Recent studies have shown that mutation at Ser522 causes inhibition of collapsin response mediator protein 2(CRMP2) phosphorylation and induces axon elongation and partial recovery of the lost sensorimotor function after spinal cord injury(SCI).We aimed to reveal the intracellular mechanism in axotomized neurons in the CRMP2 knock-in(CRMP2KI) mouse model by performing transcriptome analysis in mouse sensorimotor cortex using micro-dissection punching system.Prior to that, we analyzed the structural pathophysiology in axotomized or neighboring neurons after SCI and found that somatic atrophy and dendritic spine reduction in sensorimotor cortex were suppressed in CRMP2KI mice.Further analysis of the transcriptome has aided in the identification of four hemoglobin genes Hba-a1, Hba-a2, Hbb-bs, and Hbb-bt that are significantly upregulated in wild-type mice with concomitant upregulation of genes involved in the oxidative phosphorylation and ribosomal pathways after SCI.However, we observed substantial upregulation in channel activity genes and downregulation of genes regulating vesicles, synaptic function, glial cell differentiation in CRMP2KI mice.Moreover, the transcriptome profile of CRMP2KI mice has been discussed wherein energy metabolism and neuronal pathways were found to be differentially regulated.Our results showed that CRMP2KI mice displayed improved SCI pathophysiology not only via microtubule stabilization in neurons, but also possibly via the whole metabolic system in the central nervous system, response changes in glial cells, and synapses.Taken together, we reveal new insights on SCI pathophysiology and the regenerative mechanism of central nervous system by the inhibition of CRMP2 phosphorylation at Ser522.All these experiments were performed in accordance with the guidelines of the Institutional Animal Care and Use Committee at Waseda University, Japan(2017-A027 approved on March 21, 2017;2018-A003 approved on March 25, 2018;2019-A026 approved on March 25, 2019).
文摘Neurogenesis is the process in which neurons are generated from neural stem/progenitor cells(NSCs/NPCs).It involves the proliferation and neuronal fate specification/differentiation of NSCs,as well as migration,maturation and functional integration of the neuronal progeny into neuronal network.NSCs exhibit the two essential properties of stem cells:self-renewal and multi-potency.Contrary to previous dogma that neurogenesis happens only during development,it is generally accepted now that neurogenesis can take place throughout life in mammalian brains.This raises a new therapeutic potential of applying stem cell therapy for stroke,neurodegenerative diseases and other diseases.However,the maintenance and differentiation of NSCs/NPCs are tightly controlled by the extremely intricate molecular networks.Uncovering the underlying mechanisms that drive the differentiation,migration and maturation of specific neuronal lineages for use in regenerative medicine is,therefore,crucial for the application of stem cell for clinical therapy as well as for providing insight into the mechanisms of human neurogenesis.Here,we focus on the role of bone morphogenetic protein(BMP)signaling in NSCs during mammalian brain development.
