Spinal Muscular Atrophy (SMA) is a common inherited neurodegenerative disease caused by mutations or deletions in the SMN1 gene that encodes for the ubiquitous Survival of Motor Neuron Protein (SMN), which is essential for the assembly of spliceosomal snRNP complexes in all cells. A major unanswered question is how the loss of SMN leads to neuronal dysfunction and SMA. Further work is greatly needed to identify functions for SMN in neurons. Immunohistochemical studies have revealed localization of SMN to axons and dendrites from sections of spinal cord. Using high-resolution immunofluorescence of cultured neurons, we have shown that SMN forms granules which colocalize with RNA and ribosomes in growth cones. Using live cell imaging, we showed that EGFP-SMN granules exhibited rapid and bi-directional movements in neuronal processes and growth cones of live neurons. Primary motor neurons cultured from a transgenic mouse model of SMA displayed axonal defects that include loss of beta-actin mRNA from growth cones, suggesting a novel function for SMN in the mechanism of mRNA localization. Our preliminary data indicate that SMN associates with the mRNA binding proteins, ZBP1, ZBP2 and HuD, which are known to be involved in neuronal mRNA localization and stability. We hypothesize that these mRNA binding proteins interact with SMN to facilitate mRNA localization in processes and stabilization within growth cones. Experiments proposed here will further characterize the association, molecular interactions and dynamic regulation between SMN, HuD, ZBPs and associated mRNAs within RNA transport granules. SMN deficient motor neurons will be used to identify specific mRNAs that are altered in their localization and translation. We will investigate whether dysfunction of local mRNA regulation within SMN-deficient neurons contributes to altered growth cone motility. This research will provide new insight into neuronal functions for SMN, whereby possible defects in the assembly, localization and/or translation of mRNP complexes may contribute to the disease process in SMA.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD055835-04
Application #
7843726
Study Section
Special Emphasis Panel (ZRG1-MDCN-A (04))
Program Officer
Vitkovic, Ljubisa
Project Start
2007-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$315,437
Indirect Cost
Name
Emory University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Fallini, Claudia; Rouanet, Jeremy P; Donlin-Asp, Paul G et al. (2014) Dynamics of survival of motor neuron (SMN) protein interaction with the mRNA-binding protein IMP1 facilitates its trafficking into motor neuron axons. Dev Neurobiol 74:319-332
Xing, Lei; Bassell, Gary J (2013) mRNA localization: an orchestration of assembly, traffic and synthesis. Traffic 14:2-14
Wilhelm, Jennifer C; Xu, Mei; Cucoranu, Delia et al. (2012) Cooperative roles of BDNF expression in neurons and Schwann cells are modulated by exercise to facilitate nerve regeneration. J Neurosci 32:5002-9
Fallini, Claudia; Bassell, Gary J; Rossoll, Wilfried (2012) The ALS disease protein TDP-43 is actively transported in motor neuron axons and regulates axon outgrowth. Hum Mol Genet 21:3703-18
Fallini, Claudia; Bassell, Gary J; Rossoll, Wilfried (2012) Spinal muscular atrophy: the role of SMN in axonal mRNA regulation. Brain Res 1462:81-92
Swanger, Sharon A; Bassell, Gary J (2011) Making and breaking synapses through local mRNA regulation. Curr Opin Genet Dev 21:414-21
Peter, Cyril Jayakumar; Evans, Matthew; Thayanithy, Venugopal et al. (2011) The COPI vesicle complex binds and moves with survival motor neuron within axons. Hum Mol Genet 20:1701-11
Welshhans, Kristy; Bassell, Gary J (2011) Netrin-1-induced local ?-actin synthesis and growth cone guidance requires zipcode binding protein 1. J Neurosci 31:9800-13
Fallini, Claudia; Zhang, Honglai; Su, Yuehang et al. (2011) The survival of motor neuron (SMN) protein interacts with the mRNA-binding protein HuD and regulates localization of poly(A) mRNA in primary motor neuron axons. J Neurosci 31:3914-25
Swanger, Sharon A; Bassell, Gary J; Gross, Christina (2011) High-resolution fluorescence in situ hybridization to detect mRNAs in neuronal compartments in vitro and in vivo. Methods Mol Biol 714:103-23

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