Poster abstracts
Poster number 68 submitted by Nikaela Losievski
The role of SRP54 in motor neuron development and implications for SMA
Nikaela Losievski (Department of Neuroscience), Amy Everest, PhD (Department of Neuroscience and Department of Molecular Genetics, The Ohio State University, Columbus, OH), Thomas L. Gallagher, PhD (Department of Molecular Genetics, The Ohio State University, Columbus, OH), Alan Kessler, PhD, Christine E. Beattie, PhD (Department of Neuroscience, The Ohio State University, Columbus, OH), Sharon L. Amacher, PhD (Department of Molecular Genetics and Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH), Stephen J. Kolb, MD, PhD (Department of Biological Chemistry and Pharmacology and Department of Neurology, The Ohio State University, Columbus, OH)
Abstract:
Spinal muscular atrophy (SMA) is a motor neuron disease typically caused by a mutation in or deletion of the SMN1 gene which reduces the amount of survival of motor neuron (SMN) protein throughout an organism. All cells require SMN to survive, but the first observed symptoms in SMA patients are motor neuron dysfunction and death. It is unknown why motor neurons are especially sensitive to deficient functional SMN protein. SMN oligomerizes to form the SMN complex whose canonical function is small nuclear ribonucleoprotein (snRNP) assembly. Current research fails to demonstrate how dysfunctional snRNP assembly impacts motor neurons more severely than other tissue types. Other proposed functions for the SMN complex may explain tissue specificity in SMA. In zebrafish, tagged SMN protein was expressed under a motor neuron-specific promoter to explore SMN associations in motor neurons. One SMN-associated protein, Srp54, is a component of the signal recognition particle (SRP), an RNP responsible for processing a subset of secreted and integral membrane proteins. The SMN complex had previously been implicated in SRP assembly. If the SMN:SRP54 interaction is critical for motor neuron health, we predicted that srp54-/- zebrafish would have motor axon defects similar to smn-/-smn-/- zebrafish. We obtained a srp54-/- zebrafish line with a premature stop codon predicted to either encode a severely truncated protein or result in nonsense mediated decay of the transcript. Immunohistochemistry and confocal imaging revealed that srp54-/- embryos have truncated and/or aberrantly branched motor axons, reminiscent of the smn-/- embryos. The similar motor axon defects in the srp54-/- and smn-/- embryos support our hypothesis that an SMN:SRP association may be particularly important in motor neurons. This work will further the understanding of motor neuron selectivity in SMA and may provide insight into other motor neuron diseases.
Keywords: Spinal muscular atrophy, Motor neurons, Signal recognition particle