Gemin5 Binds to the Survival Motor Neuron mRNA to Regulate SMN Expression

Background: Spinal muscular atrophy (SMA), a neurodegenerative disease, is caused by low levels of expression of the survival motor neuron (SMN) protein. Results: Gemin5 binds to and regulates translation of the mature SMN mRNA. Conclusion: Gemin5 functions in the regulation of the SMN mRNA. Significance: Investigation of the regulation of SMN expression is critical for understanding SMA and developing therapeutics. Reduced expression of SMN causes spinal muscular atrophy, a severe neurodegenerative disease. Despite the importance of maintaining SMN levels, relatively little is known about the mechanisms by which SMN levels are regulated. We show here that Gemin5, the snRNA-binding protein of the SMN complex, binds directly to the SMN mRNA and regulates SMN expression. Gemin5 binds with high specificity, both in vitro and in vivo, to sequence and structural elements in the SMN mRNA 3-untranslated region that are reminiscent of the snRNP code to which Gemin5 binds on snRNAs. Reduction of Gemin5 redistributes the SMN mRNA from heavy polysomes to lighter polysomes and monosomes, suggesting that Gemin5 functions as an activator of SMN translation. SMN protein is not stoichiometrically present on the SMN mRNA with Gemin5, but the mRNA-binding activity of Gemin5 is dependent on SMN levels, providing a feedback mechanism for SMN to regulate its own expression via Gemin5. This work both reveals a new autoregulatory pathway governing SMN expression, and identifies a new mechanism through which SMN can modulate specific mRNA expression via Gemin5.