Modeling spinal muscular atrophy in <i>Drosophila</i> links <i>Smn</i> to FGF signaling

Sen, Anindya; Yokokura, Takakazu; Kankel, Mark W.; Dimlich, Douglas N.; Manent, Jan; Sanyal, Subhabrata; Artavanis‐Tsakonas, Spyros

doi:10.1083/jcb.201004016

Cited by 48 publications

(60 citation statements)

References 93 publications

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“…In this screen, we identified functional links between Smn and the FGF pathway (12,18), a relationship corroborated and extended by recent evidence in a severe mouse model of SMA that demonstrated widespread alterations of the FGF-system in both muscle and spinal cord (37).…”

Section: Discussionsupporting

confidence: 52%

“…Analysis of the Drosophila SMN network with DAVID identified known SMN molecular activity (alternative splicing) and SMNdependent processes ("neuron differentiation," "axon guidance," "axonogenesis," "muscle organ development," and "dendrite morphogenesis/development") ( Fig. 1C) (12,18). The predominant processes enriched in the modifier set reflect broad effects on morphogenesis and development, reinforcing the notion that Smn depletion has pleiotropic consequences.…”

Section: Resultsmentioning

confidence: 77%

“…4). This expanded human SMN network contains intermediates that are known to associate physically with SMN (GEMINs, HNRNPRs, and other small ribonucleoprotein family members) (3, 13) and signaling pathway elements known to affect SMN activity [fibroblast growth factor 2 (FGF2), glycogen synthase kinase 3 beta (GSK3B), mitogen-activated protein kinase kinase kinase 5 (MAP3K5)] (18,(35)(36)(37)(38).…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, examination of the effects of Drosophila modifiers on the Smn NMJ phenotype was used to validate their roles in Drosophila and prioritize the corresponding orthologs for further investigation in vertebrate model systems. We used NMJ assays (12,18) to sample the ability of a subset of these modifiers to alter the tubGAL4::FL26B NMJ phenotype. Examination of third instar larvae carrying a combination of tubGAL4::FL26B and each of 20 modifier strains revealed that 11 of the 20 (55%) strains show a statistically significant change in the number of synaptic boutons and are modifiers of the Smn NMJ phenotype (Fig.…”

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

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

Sen

Dimlich

Guruharsha

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Discussionsupporting

confidence: 52%

Section: Resultsmentioning

confidence: 77%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

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

Sen

Dimlich

Guruharsha

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Remarkable pleiotropy is seen for PP1 holoenzymes in distinct cellular pathways, including the EGF, TGF-b and FGF signaling pathways that have been linked to SMN (Bruns et al, 2009;Chang et al, 2008;Gangwani et al, 2001;Sen et al, 2011). Our studies reveal a regulation of the SMN complex and of nuclear body formation by PP1c, identify Gemin8 as directly interacting with PP1c, show mislocalization of PP1c and Gemin8 in SMA muscles in vivo and altered interaction of PP1c with SMN in SMA cells.…”

Section: Discussionmentioning

confidence: 77%

A role for protein phosphatase PP1γ in SMN complex formation and subnuclear localization to Cajal bodies

Renvoisé

Quérol

Verrier

et al. 2012

Journal of Cell Science

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SummaryThe spinal muscular atrophy (SMA) gene product SMN forms with gem-associated protein 2-8 (Gemin2-8) and unrip (also known as STRAP) the ubiquitous survival motor neuron (SMN) complex, which is required for the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs), their nuclear import and their localization to subnuclear domain Cajal bodies (CBs). The concentration of the SMN complex and snRNPs in CBs is reduced upon SMN deficiency in SMA cells. Subcellular localization of the SMN complex is regulated in a phosphorylation-dependent manner and the precise mechanisms remain poorly understood. Using co-immunoprecipitation in HeLa cell extracts and in vitro protein binding assays, we show here that the SMN complex and its component Gemin8 interact directly with protein phosphatase PP1c. Overexpression of Gemin8 in cells increases the number of CBs and results in targeting of PP1c to CBs. Moreover, depletion of PP1c by RNA interference enhances the localization of the SMN complex and snRNPs to CBs. Consequently, the interaction between SMN and Gemin8 increases in cytoplasmic and nuclear extracts of PP1c-depleted cells. Twodimensional protein gel electrophoresis revealed that SMN is hyperphosphorylated in nuclear extracts of PP1c-depleted cells and expression of PP1c restores these isoforms. Notably, SMN deficiency in SMA leads to the aberrant subcellular localization of Gemin8 and PP1c in the atrophic skeletal muscles, suggesting that the function of PP1c is likely to be affected in disease. Our findings reveal a role of PP1c in the formation of the SMN complex and the maintenance of CB integrity. Finally, we propose Gemin8 interaction with PP1c as a target for therapeutic intervention in SMA.

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Invertebrate models of spinal muscular atrophy: Insights into mechanisms and potential therapeutics

et al. 2011

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Invertebrate genetic models with their tractable neuromuscular systems are effective vehicles for the study of human nerve and muscle disorders. This is exemplified by insights made into spinal muscular atrophy (SMA) using the fruit fly Drosophila melanogaster and the nematode worm Caenorhabditis elegans. For speed and economy, these invertebrates offer convenient, whole-organism platforms for genetic screening as well as RNA interference (RNAi) and chemical library screens, permitting the rapid testing of hypotheses related to disease mechanisms and the exploration of new therapeutic routes and drug candidates. Here, we discuss recent developments encompassing synaptic physiology, RNA processing, and screening of compound and genome-scale RNAi libraries, showcasing the importance of invertebrate SMA models.

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Modeling spinal muscular atrophy in Drosophila links Smn to FGF signaling

Abstract: FGF signaling in neurons is regulated by Survival Motor Neuron, a component of a complex that regulates snRNP biogenesis and FGF receptor expression.

Cited by 48 publications

References 93 publications

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

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

A role for protein phosphatase PP1γ in SMN complex formation and subnuclear localization to Cajal bodies

Invertebrate models of spinal muscular atrophy: Insights into mechanisms and potential therapeutics

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