Human axonal survival of motor neuron (a-SMN) protein stimulates axon growth, cell motility, C-C motif ligand 2 (CCL2), and insulin-like growth factor-1 (IGF1) production
| Autor: | Paolo d'Errico, Denise Locatelli, Enrico Garattini, Maddalena Fratelli, Maria Monica Barzago, Silvia Capra, Adriana Zanetti, Giorgio Battaglia, Mami Kurosaki, Monica Lupi, Mineko Terao, Andrea Uggetti |
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| Rok vydání: | 2012 |
| Předmět: |
Transcription
Genetic animal diseases Motility SMN1 Biology CCL7 Biochemistry Axon Cell Line Neurobiology Cell Movement Neurite Outgrowth medicine Humans Chemokine CCL7 Insulin-Like Growth Factor I Molecular Biology Cell Shape Chemokine CCL2 Cell Proliferation Neurons Cell growth Gene Expression Profiling IGF1 Survival of motor neuron Cell Biology Spinal muscular atrophy medicine.disease Molecular biology Survival of Motor Neuron 1 Protein Axons Transport protein Cell biology nervous system diseases Motoneuron Protein Transport Cell Motility medicine.anatomical_structure nervous system Gene Expression Regulation Differentiation Spinal Muscular Atrophy Transcriptome CCL2 |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X |
| Popis: | Background: Axonal SMN is a truncated product of the spinal muscular atrophy (SMA) disease gene SMN1. Results: Forced expression of axonal SMN in motoneuron-like NSC34 cells modulates growth, axonogenesis, and motility. Conclusion: Axonal SMN induces CCL2/CCL7 chemokines and the IGF-1 growth factor. CCL2 contributes to axonal SMN-induced motility and axonogenesis. Significance: Insights into the function and underlying mechanisms with relevance for axonal SMN in SMA are provided. 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. |
| Databáze: | OpenAIRE |
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