title: Survival motor neuron function in motor axons is independent of functions required for small nuclear ribonucleoprotein biogenesis.
abstract: Spinal muscular atrophy (SMA) is a motor neuron degenerative disease caused by low levels of the survival motor neuron (SMN) protein and is linked to mutations or loss of SMN1 and retention of SMN2. How low levels of SMN cause SMA is unclear. SMN functions in small nuclear ribonucleoprotein (snRNP) biogenesis, but recent studies indicate that SMN may also function in axons. We showed previously that decreasing Smn levels in zebrafish using morpholinos (MO) results in motor axon defects. To determine how Smn functions in motor axon outgrowth, we coinjected smn MO with various human SMN RNAs and assayed the effect on motor axons. Wild-type SMN rescues motor axon defects caused by Smn reduction in zebrafish. Consistent with these defects playing a role in SMA, SMN lacking exon 7, the predominant form from the SMN2 gene, and human SMA mutations do not rescue defective motor axons. Moreover, the severity of the motor axon defects correlates with decreased longevity. We also show that a conserved region in SMN exon 7, QNQKE, is critical for motor axon outgrowth. To address the function of SMN important for motor axon outgrowth, we determined the ability of different SMN forms to oligomerization and bind Sm protein, functions required for snRNP biogenesis. We identified mutations that failed to rescue motor axon defects but retained snRNP function. Thus, we have dissociated the snRNP function of SMN from its function in motor axons. These data indicate that SMN has a novel function in motor axons that is relevant to SMA and is independent of snRNP biosynthesis.
authors.affiliation: Center for Molecular Neurobiology, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Carrel
authors.forename: Michelle L
authors.initials: ML
authors.lastname: McWhorter
authors.forename: Eileen
authors.initials: E
authors.lastname: Workman
authors.forename: Honglai
authors.initials: H
authors.lastname: Zhang
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Wolstencroft
authors.forename: Christian
authors.initials: C
authors.lastname: Lorson
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Bassell
authors.forename: Arthur H M
authors.initials: AH
authors.lastname: Burghes
authors.forename: Christine E
authors.initials: CE
authors.lastname: Beattie
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000502:physiology*; D002478:Cells, Cultured; D002642:Chick Embryo; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000502:physiology*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010641:Phenotype; D016601:RNA-Binding Proteins / Q000502:physiology*; D017411:Ribonucleoproteins, Small Nuclear / Q000096:biosynthesis* / Q000235:genetics; D055532:SMN Complex Proteins; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D015027:Zebrafish
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D017411:Ribonucleoproteins, Small Nuclear; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; C526474:smn1 protein, zebrafish