Survival Motor Neuron (SMN) protein is essential for development across metazoans, and in humans a reduction of SMN leads to Spinal Muscular Atrophy (SMA). SMA is the leading genetic cause of death in infants, characterized by degeneration of α-motor neurons and atrophy of proximal muscles. In severe cases, these children do not live past two years old. The reduction of SMN in these patients is due to mutations in the Survival Motor Neuron 1 (SMN1) gene, but how this disruption of SMN protein levels leads to SMA phenotypes is not well understood.
SMN is known to be involved in small nuclear ribonucleoprotein (snRNP) biogenesis, where it helps load Sm proteins onto snRNAs during snRNP maturation. At the same time, SMN has been implicated in alternative functions, such as mRNA transport and RNP assembly. It is unclear which SMN function is disrupted in SMA or what tissue it is disrupted in. Motor neurons and muscles are the tissues that show abnormal phenotypes in SMA patients, so it is possible that there is a cell autonomous function of SMN that is disrupted in these tissues. Another possibility is that the effect of SMN reduction is cell nonautonomous and a different cell type is losing an important function of SMN, indirectly affecting the motor neurons and muscles.
To test spatiotemporal functions of SMN, we are using Drosophila lines that contain mutations orthologous to SMA patient mutations. This set of lines has mutations in each of SMN’s functional domains: Gemin2 binding domain, Tudor domain, and self-oligomerization domain. Previously our lab has shown that these lines display a spectrum of viability phenotypes. We are using the GAL4-UAS system to express wild-type Smn in specific sets of tissues in the mutant backgrounds, then observe any changes in viability. Through these studies we will determine the minimal set of tissues that require functional Smn for proper development. We are also further characterizing these mutant lines by conducting locomotor assays and snRNP assembly assays. These assays will examine the effect of each mutated domain/residue on motor function and Smn’s canonical role in snRNP biogenesis. Through these studies we hope to determine the tissues that are severely affected by SMN reduction, and learn more about SMN’s function in these tissues.