In this study, we characterized the expression levels of NRG1-III in SMA patient tissues and in severe SMA mice and determined the impact of NRG1-III overexpression on motor axon development and disease outcomes in SMA∆7 mice. This project can provide insight into combinational therapeutic strategies with FDA approved gene therapeutics that enhance functional SMN protein translation. We have previously demonstrated that Type I SMA patients and severe SMA model mice have severe impairments of motor axon radial growth and Schwann cell ensheathment beginning prenatally that are followed by early postnatal motor unit degeneration. Neuregulin 1 type III (NRG1-III) expressed on the surface of axons and interacting with ErbB2/3 receptors on Schwann cells is critical for axon ensheathment and myelination. NRG1-III, but not NRG1-1 mRNA levels were reduced in Type I SMA patient spinal cord tissues and in symptomatic SMA mouse spinal cords. IHC showed a reduction in NRG1 staining in both human and mouse SMA ventral roots and in mouse spinal cords at symptomatic disease stages. In order to evaluate the effect of overexpression of NRG1-III on SMA disease pathogenesis, we bred mice expressing NRG1-III driven by the Thy1 promoter to SMA∆7 mice. We confirmed that both WT and SMA carrying the Thy1-NRG1-III allele overexpress NRG1-III in spinal cord tissues by immunoblotting. Both WT and SMA mice overexpressing NRG1-III showed slower weight gain and acquisition of time to right compared to non-NRG1-III overexpressing littermates indicating some general toxicity related to NRG1 overexpression. The characterization of the effects of NRG1-III overexpression on motor axon development are ongoing, but initial examination shows no change in L1 ventral root size or myelinated axon number; however there is an increase in myelin sheath thickness. Electron microscopic analysis of motor axon development at different time points is ongoing. Morphological and biochemical assessment of axonal degeneration are also ongoing. In conclusion, overexpression of NRG1-III early postnatally did not improve body weight, motor function, or survival of SMA mice despite an increase in myelin sheath thickness. These studies suggest that improving myelination alone is not sufficient to meaningfully impact the SMA disease phenotype. 
 

Acknowledgements: This work was funded by the NIH R01NS106875.