title: Cell-type-specific miR-431 dysregulation in a motor neuron model of spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is an autosomal-recessive pediatric neurodegenerative disease characterized by selective loss of spinal motor neurons. It is caused by mutation in the survival of motor neuron 1, SMN1, gene and leads to loss of function of the full-length SMN protein. microRNAs (miRNAs) are small RNAs that are involved in post-transcriptional regulation of gene expression. Prior studies have implicated miRNAs in the pathogenesis of motor neuron disease. We hypothesized that motor neuron-specific miRNA expression changes are involved in their selective vulnerability in SMA. Therefore, we sought to determine the effect of SMN loss on miRNAs and their target mRNAs in spinal motor neurons. We used microarray and RNAseq to profile both miRNA and mRNA expression in primary spinal motor neuron cultures after acute SMN knockdown. By integrating the miRNA:mRNA profiles, a number of dysregulated miRNAs were identified with enrichment in differentially expressed putative mRNA targets. miR-431 expression was highly increased, and a number of its putative mRNA targets were significantly downregulated in motor neurons after SMN loss. Further, we found that miR-431 regulates motor neuron neurite length by targeting several molecules previously identified to play a role in motor neuron axon outgrowth, including chondrolectin. Together, our findings indicate that cell-type-specific dysregulation of miR-431 plays a role in the SMA motor neuron phenotype.
authors.affiliation: Department of Neurology, The F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Mary H
authors.initials: MH
authors.lastname: Wertz
authors.affiliation: Department of Neurology, The F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Kellen
authors.initials: K
authors.lastname: Winden
authors.affiliation: Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
authors.forename: Pierre
authors.initials: P
authors.lastname: Neveu
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA Neurotherapeutics Laboratory, Institute of Molecular and Cell Biology, A*STAR, Singapore 138673, Singapore.
authors.forename: Shi-Yan
authors.initials: SY
authors.lastname: Ng
authors.affiliation: Department of Neurology, The F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Ebru
authors.initials: E
authors.lastname: Ercan
authors.affiliation: Department of Neurology, The F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA mustafa.sahin@childrens.harvard.edu.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Sahin
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D046228:Microarray Analysis; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000503:physiopathology; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics*
chemical_list: C000599703:MIRN431 microRNA, mouse; D035683:MicroRNAs; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein