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Genetic Circuitry of Survival Motor Neuron, the Gene Underlying Spinal

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Genetic Circuitry of Survival Motor Neuron, the Gene Underlying Spinal Genetic circuitry of Survival motor neuron, the gene PNAS PLUS underlying spinal muscular atrophy Anindya Sena,1, Douglas N. Dimlicha,1, K. G. Guruharshaa,1, Mark W. Kankela,1, Kazuya Horia, Takakazu Yokokuraa,3, Sophie Brachatb,c, Delwood Richardsonb, Joseph Loureirob, Rajeev Sivasankaranb, Daniel Curtisb, Lance S. Davidowd, Lee L. Rubind, Anne C. Harte, David Van Vactora, and Spyros Artavanis-Tsakonasa,2 aDepartment of Cell Biology, Harvard Medical School, Boston, MA 02115; bDevelopmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, MA 02139; cMusculoskeletal Diseases, Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland; dDepartment of Stem Cell and Regenerative Biology, Harvard Medical School, Boston, MA 02115; and eDepartment of Neuroscience, Brown University, Providence, RI 02912 Edited by Jeffrey C. Hall, University of Maine, Orono, ME, and approved May 7, 2013 (received for review February 13, 2013) The clinical severity of the neurodegenerative disorder spinal muscu- snRNP biogenesis, the molecular functionality that is most clearly lar atrophy (SMA) is dependent on the levels of functional Survival associated with SMN. Motor Neuron (SMN) protein. Consequently, current strategies for As the human disease state results from partial loss of SMN developing treatments for SMA generally focus on augmenting SMN function, we reasoned that a screening paradigm using a hypo- levels. To identify additional potential therapeutic avenues and morphic Smn background (as opposed to a background that achieve a greater understanding of SMN, we applied in vivo, in vitro, completely eliminates SMN function) would more closely resemble and in silico approaches to identify genetic and biochemical interac- the genetic condition in SMA. Such a screen would therefore en- tors of the Drosophila SMN homolog. We identified more than 300 hance our ability to detect elements of the Smn genetic network candidate genes that alter an Smn-dependent phenotype in vivo. In- and, consequently, add significantly to our efforts to both dissect the tegrating the results from our genetic screens, large-scale protein in- Smn genetic circuitry and identify clinically relevant targets with teraction studies, and bioinformatic analysis, we define a unique mode of action. interactome for SMN that provides a knowledge base for a better This complementary screen proved to be more sensitive than our understanding of SMA. previous screen and led to the identification of over 300 genetic in- GENETICS teractors. Taking advantage of the recently established Drosophila proteomics | disease model | neurodegeneration | Protein Interaction Map (DPiM) (13), we related the newly neuromuscular junction | ALS identified genetic interactors to the SMN protein interactome, producing an integrated Drosophila SMN biological network. Fi- pinal muscular atrophy (SMA), the leading genetic cause of nally, the Drosophila SMN network was evaluated for its relevance Sinfant mortality, results from the partial loss of Survival Motor to human biology by mapping Drosophila SMN network genes to Neuron (SMN) gene activity (1). Numerous studies indicate that their human homologs and analyzing the human network using SMN functions as a central component of a complex that is re- computational biology tools. The projection of the Drosophila sponsible for the assembly of spliceosomal small nuclear ribonu- SMN network derived from this study onto the human network cleoproteins (snRNPs) (reviewed in ref. 2). SMN is also reported derived from prior knowledge provides a rational basis for SMN to play additional roles, including mRNA trafficking in the axon functional hypotheses and network intervention points that carry (3). In humans, SMN is encoded by two nearly identical genes, potential for so-far-unexplored clinical applications. SMN1 and SMN2, which are located on chromosome 5 (4). SMN2 fi differs from SMN1 in that only 10% of SMN2 transcripts produce Signi cance functional SMN due to a single-nucleotide polymorphism that results in inefficient splicing of exon 7 and translation of a trun- Spinal muscular atrophy (SMA), the leading genetic cause of cated, unstable SMN protein (1, 5, 6). The clinical severity of SMA infant mortality, is a devastating neurodegenerative disease correlates with the SMN2 copy number, which varies between caused by reduced levels of Survival Motor Neuron (SMN) gene individuals (7). As the small amount of functional SMN2 protein activity. Despite well-characterized aspects of the involvement produced by each copy of the gene is capable of partially com- of SMN in small nuclear ribonucleoprotein biogenesis, the gene pensating for the loss of the SMN1 gene function, higher copy circuitry affecting SMN activity remains obscure. Here, we use Drosophila as a model system to integrate results from large- numbers of SMN2 typically result in milder forms of SMA. fi scale genetic and proteomic studies and bioinformatic analyses Therefore, genetic modi ers capable of increasing the abundance fi fi to de ne a unique SMN interactome to provide a basis for and/or speci c activity of SMN hold promise as therapeutic targets. a better understanding of SMA. Such efforts not only help The Drosophila genome harbors a single, highly conserved dissect Smn biology but also may point to potential clinically ortholog of SMN1/2, the Smn gene. SMN is essential for cell via- relevant targets. bility in vertebrates and Drosophila (8, 9). In Drosophila, zygotic loss of Smn function results in recessive larval lethality (not em- Author contributions: A.S., D.N.D., M.W.K., D.C., L.L.R., D.V.V., and S.A.-T. designed re- bryonic as might be expected) due to the rescue of early de- search; A.S., D.N.D., K.G.G., M.W.K., K.H., and T.Y. performed research; D.N.D., K.G.G., velopment by maternal contribution of Smn. The larval phenotype S.B., D.R., J.L., R.S., D.C., L.S.D., L.L.R., A.C.H., and D.V.V. contributed new reagents/ana- lytic tools; A.S., D.N.D., K.G.G., M.W.K., S.B., D.R., J.L., R.S., L.S.D., A.C.H., and S.A.-T. includes neuromuscular junction (NMJ) abnormalities that are analyzed data; and A.S., D.N.D., K.G.G., M.W.K., S.B., D.C., and S.A.-T. wrote the paper. reminiscent of those associated with the human disease, rendering The authors declare no conflict of interest. this invertebrate organism an excellent system to model SMN bi- This article is a PNAS Direct Submission. – ology (9 11). We previously described a genetic screen for modi- 1A.S., D.N.D., K.G.G., and M.W.K. contributed equally to this work. fiers of the lethal phenotype resulting from a complete loss- 2To whom correspondence should be addressed. E-mail: [email protected]. of-function Smn allele (12). This screen, although it probed half of 3 fi Present address: Okinawa Science and Technology Graduate University, Onna-son, the Drosophila genome, identi ed only a relatively small number of Okinawa 904-0495, Japan. genes that affected the NMJ phenotype associated with Smn loss This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. of function (12). In particular, it did not identify genes involved in 1073/pnas.1301738110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1301738110 PNAS | Published online June 11, 2013 | E2371–E2380 Downloaded by guest on September 30, 2021 Results FL26B genetic background resulted in enhancement or suppres- Genetic Screen for Modifiers of Smn-Dependent Lethality. We ex- sion, respectively (Fig. 1A). In addition, the ability of wild-type amined several Smn-RNAi strains under the control of the yeast Smn (expressed by a UAS-Smn-GFP transgene) to rescue the le- upstream activation sequence (UAS) to identify a hypomorphic thality indicates that this phenotype does not result from off-target Smn allele that could be used to model SMA in Drosophila more RNAi effects. These results were corroborated using an in- faithfully than alleles that completely abolish Smn function. We dependent Smn RNAi strain. Finally, we demonstrated that pre- identified a transgenic strain, UAS-Smn-RNAiFL26B (FL26B), that viously identified Smn modifiers altered the Smn RNAi displays a less severe phenotype than the allele used in our previous phenotype in the expected fashion (Fig. 1A). Together, these screen (12). Specifically, expression of FL26B under the control results demonstrate that the tubGAL4::FL26B phenotype is useful of tubulinGAL4 (tubGAL4::FL26B) results in late pupal le- in detecting changes in Smn functional activity and is thus thality whereby ∼50% of the pupae reach a more mature (pig- asuitableassayonwhichtobaseamodifier screen that will mented) developmental stage before death than their less define and dissect the Smn genetic network. mature, unpigmented siblings (Fig. 1A). Using this assay, we screened the Exelixis collection of ge- We determined that this phenotype, measured by the ratio of nome-wide insertional mutations (http://drosophila.med.harvard. pigmented to unpigmented pupae, is sensitive to Smn gene dosage, edu) (14, 15) for dominant modification of the lethality associ- as reducing or increasing Smn copy number in the tubGAL4:: ated with the tubGAL4::FL26B strain (see Fig. 1B for scheme) A B P{tubP-Gal4}LL7 e 100% w1118 ; P{UAS-Smn-RNAi}FL26B ; TM6B, P{tubP-Gal80}OV3 Hu Tb e 80% 60% w1118 40% ;; TE{Exelixis} F1 20% P{tubP-Gal4}LL7 e w1118 ; P{UAS-Smn-RNAi}FL26B ; 0% TE{Exelixis} Count pigmented and unpigmented Control d02492 d09801 f05549 c05057 Smn pupae (Tb) and adult escaper (Hu) Smn rescue Smn deficiency pigmented
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