Active transport of the survival motor neuron protein and the role of exon-7 in cytoplasmic localization

Honglai L. Zhang, Feng Pan, Daewha Hong, Shailesh M. Shenoy, Robert H. Singer, Gary J. Bassell

Research output: Contribution to journalArticle

219 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6627-6637
Number of pages11
JournalJournal of Neuroscience
Volume23
Issue number16
StatePublished - Jul 23 2003

Keywords

  • Active transport
  • Growth cone
  • Neurite outgrowth
  • Spinal muscular atrophy
  • Survival motor neuron protein
  • mRNA localization
  • mRNA transport

ASJC Scopus subject areas

  • Neuroscience(all)

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