title: Active transport of the survival motor neuron protein and the role of exon-7 in cytoplasmic localization.
abstract: Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by deletion and/or mutation of the survival motor neuron protein Gene (SMN1) that results in the expression of a truncated protein lacking the C terminal exon-7. Whereas SMN has been shown to be an important component of diverse ribonucleoprotein (RNP) complexes, its function in neurons is unknown. We hypothesize that the active transport of SMN may be important for neurite outgrowth and that disruption of exon-7 could impair its normal intracellular trafficking. SMN was localized in granules that were associated with cytoskeletal filament systems and distributed throughout neurites and growth cones. Live cell imaging of enhanced green fluorescent protein (EGFP)-SMN granules revealed rapid, bidirectional and cytoskeletal-dependent movements. Exon-7 was necessary for localization of SMN into the cytoplasm but was not sufficient for granule formation and transport. A cytoplasmic targeting signal within exon-7 was identified that could completely redistribute the nuclear protein D-box binding factor 1 into the cytoplasm. Neurons transfected with SMN lacking exon-7 had significantly shorter neurites, a defect that could be rescued by redirecting the exon-7 deletion mutant into neurites by a targeting sequence from growth-associated protein-43. These findings provide the first demonstration of cytoskeletal-based active transport of SMN in neuronal processes and the function of exon-7 in cytoplasmic localization. Such observations provide motivation to investigate possible transport defects or inefficiency of SMN associated RNPs in motor neuron axons in SMA.
authors.affiliation: Department of Neuroscience, Rose F. Kennedy Center for Mental Retardation, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Honglai L
authors.initials: HL
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Pan
authors.forename: Daewha
authors.initials: D
authors.lastname: Hong
authors.forename: Shailesh M
authors.initials: SM
authors.lastname: Shenoy
authors.forename: Robert H
authors.initials: RH
authors.lastname: Singer
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Bassell
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002642:Chick Embryo; D017362:Cyclic AMP Response Element-Binding Protein; D003593:Cytoplasm / Q000378:metabolism*; D003594:Cytoplasmic Granules / Q000378:metabolism; D005091:Exons / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D017930:Genes, Reporter; D020439:Growth Cones / Q000378:metabolism; D006801:Humans; D008870:Microtubules / Q000502:physiology; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D016601:RNA-Binding Proteins; D051381:Rats; D055532:SMN Complex Proteins; D017384:Sequence Deletion; D055533:Survival of Motor Neuron 1 Protein
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526473:Smn1 protein, rat; D055533:Survival of Motor Neuron 1 Protein