Survival Motor Neuron Function in Motor Axons Is Independent of Functions Required for Small Nuclear Ribonucleoprotein Biogenesis
| Autor: | Arthur H.M. Burghes, Michelle L. McWhorter, Elizabeth C. Wolstencroft, Christine E. Beattie, Tessa L. Carrel, Christian L. Lorson, Gary J. Bassell, Eileen Workman, Honglai Zhang |
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| Rok vydání: | 2006 |
| Předmět: |
animal diseases
Molecular Sequence Data Nerve Tissue Proteins Chick Embryo SMN1 Biology medicine Animals Humans snRNP Amino Acid Sequence Axon Cyclic AMP Response Element-Binding Protein Cells Cultured Zebrafish SnRNP Biogenesis Motor Neurons General Neuroscience RNA-Binding Proteins SMN Complex Proteins Articles Spinal muscular atrophy Motor neuron Ribonucleoproteins Small Nuclear SMA medicine.disease Survival of Motor Neuron 1 Protein Axons nervous system diseases Survival of Motor Neuron 2 Protein Phenotype medicine.anatomical_structure nervous system Mutation Neuroscience Small nuclear ribonucleoprotein |
| Zdroj: | The Journal of Neuroscience. 26:11014-11022 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.1637-06.2006 |
| Popis: | 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 ofSMN1and retention ofSMN2. 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 coinjectedsmnMO with various humanSMNRNAs 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 theSMN2gene, 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. |
| Databáze: | OpenAIRE |
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