title: Subcellular transcriptome alterations in a cell culture model of spinal muscular atrophy point to widespread defects in axonal growth and presynaptic differentiation.
abstract: Neuronal function critically depends on coordinated subcellular distribution of mRNAs. Disturbed mRNA processing and axonal transport has been found in spinal muscular atrophy and could be causative for dysfunction and degeneration of motoneurons. Despite the advances made in characterizing the transport mechanisms of several axonal mRNAs, an unbiased approach to identify the axonal repertoire of mRNAs in healthy and degenerating motoneurons has been lacking. Here we used compartmentalized microfluidic chambers to investigate the somatodendritic and axonal mRNA content of cultured motoneurons by microarray analysis. In axons, transcripts related to protein synthesis and energy production were enriched relative to the somatodendritic compartment. Knockdown of Smn, the protein deficient in spinal muscular atrophy, produced a large number of transcript alterations in both compartments. Transcripts related to immune functions, including MHC class I genes, and with roles in RNA splicing were up-regulated in the somatodendritic compartment. On the axonal side, transcripts associated with axon growth and synaptic activity were down-regulated. These alterations provide evidence that subcellular localization of transcripts with axonal functions as well as regulation of specific transcripts with nonautonomous functions is disturbed in Smn-deficient motoneurons, most likely contributing to the pathophysiology of spinal muscular atrophy.
authors.affiliation: Institute for Clinical Neurobiology, University of Wuerzburg, D 97078 Wuerzburg, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Saal
authors.affiliation: Institute for Clinical Neurobiology, University of Wuerzburg, D 97078 Wuerzburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Briese
authors.affiliation: Department of Physiological Chemistry I, Biocenter, University of Wuerzburg, D 97074 Wuerzburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Kneitz
authors.affiliation: Institute for Clinical Neurobiology, University of Wuerzburg, D 97078 Wuerzburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Glinka
authors.affiliation: Institute for Clinical Neurobiology, University of Wuerzburg, D 97078 Wuerzburg, Germany Sendtner_M@ukw.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Sendtner
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000378:metabolism*; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics* / Q000378:metabolism*; D059467:Transcriptome
chemical_list: C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein
keywords: axon; compartment; motoneuron; spinal muscular atrophy