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.
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.
Molecular Neuroanatomy Laboratory, Department of Experimental Neurophysiology and Epileptology, Istituto Neurologico "C. Besta," via Celoria 11, 20133 Milano, Italy.
Denise
D
Locatelli
Mineko
M
Terao
Maddalena
M
Fratelli
Adriana
A
Zanetti
Mami
M
Kurosaki
Monica
M
Lupi
Maria Monica
MM
Barzago
Andrea
A
Uggetti
Silvia
S
Capra
Paolo
P
D'Errico
Giorgio S
GS
Battaglia
Enrico
E
Garattini
D001369:Axons / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D048430:Cell Shape; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D054410:Chemokine CCL7 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D021381:Protein Transport; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014158:Transcription, Genetic; D059467:Transcriptome
C111835:CCL2 protein, human; C515450:CCL7 protein, human; D018932:Chemokine CCL2; D054410:Chemokine CCL7; C526471:SMN1 protein, human; D055533:Survival of Motor Neuron 1 Protein; D007334:Insulin-Like Growth Factor I