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Spinal muscular atrophy (SMA) is an inherited neurodegenerative disease caused by homozygous inactivation of the  SMN1  gene and reduced levels of the survival motor neuron (SMN) protein. Since higher copy numbers of the nearly identical  SMN2  gene reduce disease severity, to date most efforts to develop a therapy for SMA have focused on enhancing SMN expression. Identification of alternative therapeutic approaches has partly been hindered by limited knowledge of potential targets and the lack of cell-based screening assays that serve as readouts of SMN function. Here, we established a cell system in which proliferation of cultured mouse fibroblasts is dependent on functional SMN produced from the  SMN2  gene. To do so, we introduced the entire human  SMN2  gene into NIH3T3 cell lines in which regulated knockdown of endogenous mouse Smn severely decreases cell proliferation. We found that low  SMN2  copy number has modest effects on the cell proliferation phenotype induced by Smn depletion, while high  SMN2  copy number is strongly protective. Additionally, cell proliferation correlates with the level of SMN activity in small nuclear ribonucleoprotein assembly. Following miniaturization into a high-throughput format, our cell-based phenotypic assay accurately measures the beneficial effects of both pharmacological and genetic treatments leading to SMN upregulation. This cell model provides a novel platform for phenotypic screening of modifiers of SMN2 gene expression and function that act through multiple mechanisms, and a powerful new tool for studies of SMN biology and SMA therapeutic development.

A Cell System for Phenotypic Screening of Modifiers of SMN2 Gene Expression and Function