Integration of Retrograde Axonal and Nuclear Transport Mechanisms in Neurons: Implications for Therapeutics

The elongated morphology of neuronal processes imposes a significant challenge for effective intracellular communication between the neurites and the cell body. This problem is especially acute upon injury, when the cell body must receive accurate and timely information on the site and extent of axonal damage to mount an appropriate response. Recent work has demonstrated that nuclear import factors from the importin (karyopherin) α and β families provide a mechanism for retrograde injury signaling. Importins are found throughout axons and dendrites at significant distances from the cell body, and importin β protein is increased after nerve lesion by local translation of axonal mRNA. This leads to formation of a high-affinity nuclear localization signal (NLS) binding complex that traffics retrogradely due to an interaction of importin α with the motor protein dynein. Disruption of the complex with excess NLS peptides delays regeneration of injured sensory neurons. The dual role of importins in retrograde transport in axons and nuclear import in cell bodies suggests new avenues for manipulating intrinsic regeneration mechanisms in the nervous system and may provide a novel route for drug delivery to the CNS.

[1]  R. Ambron,et al.  Pathways that elicit long-term changes in gene expression in nociceptive neurons following nerve injury: contributions to neuropathic pain , 2004, Neurological research.

[2]  M. Tuszynski,et al.  Nucleus hears axon's pain , 2004, Nature Medicine.

[3]  L. Benowitz,et al.  Counteracting the Nogo Receptor Enhances Optic Nerve Regeneration If Retinal Ganglion Cells Are in an Active Growth State , 2004, The Journal of Neuroscience.

[4]  R. Vallee,et al.  Dynein: An ancient motor protein involved in multiple modes of transport. , 2004, Journal of neurobiology.

[5]  A. Burlingame,et al.  From snails to sciatic nerve: Retrograde injury signaling from axon to soma in lesioned neurons. , 2004, Journal of neurobiology.

[6]  G. Raisman.  Myelin inhibitors: does NO mean GO? , 2004, Nature Reviews Neuroscience.

[7]  L. Goldstein,et al.  Cargo-carrying motor vehicles on the neuronal highway: transport pathways and neurodegenerative disease. , 2004, Journal of neurobiology.

[8]  M. Chao,et al.  Mechanisms of neurotrophin receptor vesicular transport. , 2004, Journal of neurobiology.

[9]  M. Koltzenburg,et al.  Axoplasmic Importins Enable Retrograde Injury Signaling in Lesioned Nerve , 2003, Neuron.

[10]  C. Woolf,et al.  Central sensitization and LTP: do pain and memory share similar mechanisms? , 2003, Trends in Neurosciences.

[11]  M. Mason,et al.  Corticospinal neurons up‐regulate a range of growth‐associated genes following intracortical, but not spinal, axotomy , 2003, The European journal of neuroscience.

[12]  T. Ho,et al.  Simple mimetics of a nuclear localization signal (NLS). , 2003, Organic letters.

[13]  J. Goldberg.  How does an axon grow? , 2003, Genes & development.

[14]  Karsten Weis,et al.  Regulating Access to the Genome Nucleocytoplasmic Transport throughout the Cell Cycle , 2003, Cell.

[15]  Marco Domeniconi,et al.  New roles for old proteins in adult CNS axonal regeneration , 2003, Current Opinion in Neurobiology.

[16]  W. Mobley,et al.  Traffic at the intersection of neurotrophic factor signaling and neurodegeneration , 2003, Trends in Neurosciences.

[17]  C. Echeverri,et al.  Function of dynein and dynactin in herpes simplex virus capsid transport. , 2002, Molecular biology of the cell.

[18]  L. Parada,et al.  The Molecular and Genetic Basis of Neurological Tumours , 2002, Nature Reviews Cancer.

[19]  A. Giuditta,et al.  Axonal and presynaptic protein synthesis: new insights into the biology of the neuron , 2002, Trends in Neurosciences.

[20]  J. Flanagan,et al.  Axonal Protein Synthesis Provides a Mechanism for Localized Regulation at an Intermediate Target , 2002, Cell.

[21]  W. Snider,et al.  Signaling the Pathway to Regeneration , 2002, Neuron.

[22]  F. Rossi,et al.  Long-Term Injured Purkinje Cells Are Competent for Terminal Arbor Growth, but Remain Unable to Sustain Stem Axon Regeneration , 2002, Experimental Neurology.

[23]  D. Ginty,et al.  Retrograde neurotrophin signaling: Trk-ing along the axon , 2002, Current Opinion in Neurobiology.

[24]  W. Pardridge,et al.  Drug and gene targeting to the brain with molecular trojan horses , 2002, Nature Reviews Drug Discovery.

[25]  C. Holt,et al.  Chemotropic Responses of Retinal Growth Cones Mediated by Rapid Local Protein Synthesis and Degradation , 2001, Neuron.

[26]  K. Moses,et al.  Perturbing nuclear transport in Drosophila eye imaginal discs causes specific cell adhesion and axon guidance defects. , 2001, Developmental biology.

[27]  R. Standaert,et al.  A photoregulated ligand for the nuclear import receptor karyopherin alpha. , 2001, Bioorganic & medicinal chemistry.

[28]  K. Martin,et al.  A Functional Role for Intra-Axonal Protein Synthesis during Axonal Regeneration from Adult Sensory Neurons , 2001, The Journal of Neuroscience.

[29]  L. Barrett,et al.  Gene therapy for central nervous system repair. , 2001, Current opinion in molecular therapeutics.

[30]  C. Kaltschmidt,et al.  Retrograde Transport of Transcription Factor NF-κB in Living Neurons* , 2001, The Journal of Biological Chemistry.

[31]  R. Ambron,et al.  Positive injury signals induce growth and prolong survival in Aplysia neurons. , 2000, Journal of neurobiology.

[32]  R. Ambron,et al.  A nuclear localization signal targets proteins to the retrograde transport system, thereby evading uptake into organelles in aplysia axons. , 1997, Journal of Neurobiology.

[33]  Deanna S. Smith,et al.  A Transcription-Dependent Switch Controls Competence of Adult Neurons for Distinct Modes of Axon Growth , 1997, The Journal of Neuroscience.

[34]  E. Walters,et al.  Intrinsic Injury Signals Enhance Growth, Survival, and Excitability of Aplysia Neurons , 1996, The Journal of Neuroscience.

[35]  T. Torgerson,et al.  Inhibition of Nuclear Translocation of Transcription Factor NF-κB by a Synthetic Peptide Containing a Cell Membrane-permeable Motif and Nuclear Localization Sequence (*) , 1995, The Journal of Biological Chemistry.

[36]  Brian J. Wiltgen,et al.  NF-kappa B functions in synaptic signaling and behavior. , 2003, Nature neuroscience.

[37]  F. Gage,et al.  Targeted retrograde gene delivery for neuronal protection. , 2002, Molecular therapy : the journal of the American Society of Gene Therapy.

[38]  J. Fawcett,et al.  Chondroitin sulphate proteoglycans in the CNS injury response. , 2002, Progress in brain research.

[39]  E. Walters,et al.  Priming events and retrograde injury signals. A new perspective on the cellular and molecular biology of nerve regeneration. , 1996, Molecular Neurobiology.