Human axonal Survival of Motor Neuron (a-SMN) protein stimulates axon growth, cell motility, C-C motif ligand 2 (CCL2),andinsulin-like growth factor-1 (IGF1) production

Denise Locatelli, Mineko Terao, Maddalena Fratelli, Adriana Zanetti, Mami Kurosaki, Monica Lupi, Maria Monica Barzago, Andrea Uggetti, Silvia Capra, Paolo D'Errico, Giorgio S. Battaglia, Enrico Garattini

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Spinal muscular atrophy is a fatal genetic disease of motoneurons due to loss of full-length survival of motor neuron protein, the main product of the disease gene SMN1. Axonal SMN (a-SMN) is an alternatively spliced isoform of SMN1, generated by retention of intron 3. To study a-SMN function, we generated cellular clones for the expression of the protein in mouse motoneuron-like NSC34 cells. The model was instrumental in providing evidence that a-SMN decreases cell growth and plays an important role in the processes of axon growth and cellular motility. In our conditions, low levels of a-SMN expression were sufficient to trigger the observed biological effects, which were not modified by further increasing the amounts of the expressed protein. Differential transcriptome analysis led to the identification of novel a-SMN-regulated factors, i.e. the transcripts coding for the two chemokines, C-C motif ligands 2 and 7 (CCL2 and CCL7), as well as the neuronal and myotrophic factor, insulin-like growth factor-1 (IGF1). a-SMN-dependent induction of CCL2 and IGF1 mRNAs resulted in increased intracellular levels and secretion of the respective protein products. Induction of CCL2 contributes to the a-SMN effects, mediating part of the action on axon growth and random cell motility, as indicated by chemokine knockdown and re-addition studies. Our results shed new light on a-SMN function and the underlying molecular mechanisms. The data provide a rational framework to understand the role of a-SMN deficiency in the etiopathogenesis of spinal muscular atrophy.

Original languageEnglish
Pages (from-to)25782-25794
Number of pages13
JournalJournal of Biological Chemistry
Issue number31
Publication statusPublished - Jul 27 2012

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology


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