Genetic circuitry of Survival motor neuron , the gene underlying spinal muscular atrophy

Abstract

The clinical severity of the neurodegenerative disorder spinal muscular atrophy (SMA) is dependent on the levels of functional Survival Motor Neuron (SMN) protein. Consequently, current strategies for developing treatments for SMA generally focus on augmenting SMN levels. To identify additional potential therapeutic avenues and achieve a greater understanding of SMN, we applied in vivo, in vitro, and in silico approaches to identify genetic and biochemical interactors of the Drosophila SMN homolog. We identified more than 300 candidate genes that alter an Smn-dependent phenotype in vivo. Integrating the results from our genetic screens, large-scale protein interaction studies, and bioinformatic analysis, we define a unique interactome for SMN that provides a knowledge base for a better understanding of SMA.pinal muscular atrophy (SMA), the leading genetic cause of infant mortality, results from the partial loss of Survival Motor Neuron (SMN) gene activity (1). Numerous studies indicate that SMN functions as a central component of a complex that is responsible for the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) (reviewed in ref.2). SMN is also reported to play additional roles, including mRNA trafficking in the axon (3). In humans, SMN is encoded by two nearly identical genes, SMN1 and SMN2, which are located on chromosome 5 (4). SMN2 differs from SMN1 in that only 10% of SMN2 transcripts produce functional SMN due to a single-nucleotide polymorphism that results in inefficient splicing of exon 7 and translation of a truncated, unstable SMN protein (1,5,6). The clinical severity of SMA correlates with the SMN2 copy number, which varies between individuals (7). As the small amount of functional SMN2 protein produced by each copy of the gene is capable of partially compensating for the loss of the SMN1 gene function, higher copy numbers of SMN2 typically result in milder forms of SMA. Therefore, genetic modifiers capable of increasing the abundance and/or specific activity of SMN hold promise as therapeutic targets.The Drosophila genome harbors a single, highly conserved ortholog of SMN1/2, the Smn gene. SMN is essential for cell viability in vertebrates and Drosophila (8, 9). In Drosophila, zygotic loss of Smn function results in recessive larval lethality (not embryonic as might be expected) due to the rescue of early development by maternal contribution of Smn. The larval phenotype includes neuromuscular junction (NMJ) abnormalities that are reminiscent of those associated with the human disease, rendering this invertebrate organism an excellent system to model SMN biology (9-11). We previously described a genetic screen for modifiers of the lethal phenotype resulting from a complete lossof-function Smn allele (12). This screen, although it probed half of the Drosophila genome, identified only a relatively small number of genes that affected the NMJ phenotype associated with Smn loss of function (12). In particular, it did not identify genes involved in snRNP biogenesis, the molecular func...

The survival motor neuron genesmn-1interacts with the U2AF large subunit geneuaf-1to regulateCaenorhabditis eleganslifespan and motor functions

“…We also suggest that mutations of the U2AF large subunit gene uaf-1 might be protective modifiers of smn-1 loss-of-function mutants. Together with previous studies of other SMN modifiers, 18,[26][27][28][29][30]45 our findings should facilitate the understanding of SMN functions.…”

“…27 Recently numerous interactors of SMN have been identified in Drosophila and C. elegans. [28][29][30] It remains unclear how these genes interact with Drosophila and C. elegans orthologs of SMN and whether these genes contribute to the defects of SMN-deficient mutants.…”

Drosophila Syncrip modulates the expression of mRNAs encoding key synaptic proteins required for morphology at the neuromuscular junction

“…Recent work has revealed that SYN-CRIP/hnRNPQ and Fragile X mental retardation protein (FMRP) are present in the same mRNP granule (Chen et al 2012), and loss of expression of FMRP or the ability of FMRP to interact with mRNA and polysomes can cause cases of Fragile X syndrome. Separate studies have also shown that SYNCRIP interacts with wild-type survival of motor neuron (SMN) protein but not the truncated or mutant forms found to cause spinal muscular atrophy (Rossoll et al 2002), and Syp genetically interacts with Smn mutations in vivo (Sen et al 2013). Understanding Syp function in the regulation of such diverse and complex targets may, therefore, provide new avenues for understanding the molecular basis of complex disease phenotypes and potentially lead to future therapeutic approaches.…”

Assays for the Identification and Prioritization of Drug Candidates for Spinal Muscular Atrophy

“…Genetic modifiers of the phenotypes arising from SMN deficiency in Drosophila and Caenorhabditis elegans have also been identified. 115,116 The identification of genetic modifiers and downstream targets of SMN, once validated and shown to improve phenotypes in established mouse models of SMA, will uncover a wide array of potential new drug targets for SMA to be directly assayed and screened. To date, however, most cell-based assays to identify novel SMA drugs have been designed to assess SMN2 expression.…”