Survival Motor Neuron (SMN) function in motoneuron development

Ohio State University, Columbus OH

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Abstract

? DESCRIPTION (provided by applicant): The goal of our work is to elucidate the function of the Survival Motor Neuron (SMN) protein in motoneuron development. This is an essential question because SMN is linked to the motoneuron disease Spinal Muscular Atrophy (SMA). SMA leads to paralysis and early death of infants/children. Work in SMA animal models and analysis of SMA patient autopsy tissue has revealed that motoneurons develop abnormally and fail to form axons correctly under disease conditions of low SMN. There is a critical need, therefore, to understand SMN function in motoneuron and motor axon development. Our previous work on SMN has lent insight into this process. We have shown in zebrafish genetic models that smn mutants have motor axon outgrowth defects including decreased motor axon filopodia, dramatically fewer axonal branches, and fewer neuromuscular junction synapses. We have also shown that SMN is localized to motor axons and its presence there is developmentally regulated. SMN binds a number of different mRNA binding proteins (RBPs) that are involved in localizing mRNAs into axons and growth cones. Localized mRNA translation functions in developing axons and controls axon guidance decisions, branching and outgrowth. In preliminary data we have validated that SMN binds the neuron specific RBP HuD in motoneurons and this interaction is developmentally regulated. We have also generated HuD mutants and find that they have motor axon defects. Based on these data we hypothesize that SMN localization to motor axons is critical for axonal development. We propose that SMN is a master regulator of RBP mRNA assembly to facilitate RNA localization to growing axons. To test this hypothesis, we will determine the complement of SMN:RBP complexes specifically in motoneurons and whether these complexes are developmentally regulated. We will use SMN variants (including a patient mutation) to elucidate relevant RBP binding domains. We will generate RBP mutants and characterize whether they have motor axon defects by analyzing developmental outgrowth and filopodial dynamics. We will determine whether motoneuron autonomous expression of these RBPs can rescue any motor axon defects. Lastly, we will test whether mRNA expression in motor axons is affected by SMN and RBP mutants. We will reveal whether SMN or SMN variants can rescue these defects and whether this is linked to rescue of motor axon outgrowth. Together these experiments will rigorously test the innovative concept that SMN is a master regulator of RBP complex assembly needed for localized mRNA transport to axons critical for developmental motor axon outgrowth. Knowledge gained from these key experiments will be impactful both towards our understanding of basic mechanisms in motor axon biology and towards our understanding of phenotypes associated with motoneuron disease.