{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:57:08Z","timestamp":1791194228787,"version":"4.1.0"},"reference-count":79,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2014,2,1]],"date-time":"2014-02-01T00:00:00Z","timestamp":1391212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Drosophila melanogaster has been widely used as a model of human Mendelian disease, but its value in modeling complex disease has received little attention. Fly models of complex disease would enable high-resolution mapping of disease-modifying loci and the identification of novel targets for therapeutic intervention. Here, we describe a fly model of permanent neonatal diabetes mellitus and explore the complexity of this model. The approach involves the transgenic expression of a misfolded mutant of human preproinsulin, hINSC96Y, which is a cause of permanent neonatal diabetes. When expressed in fly imaginal discs, hINSC96Y causes a reduction of adult structures, including the eye, wing, and notum. Eye imaginal discs exhibit defects in both the structure and the arrangement of ommatidia. In the wing, expression of hINSC96Y leads to ectopic expression of veins and mechano-sensory organs, indicating disruption of wild-type signaling processes regulating cell fates. These readily measurable \u201cdisease\u201d phenotypes are sensitive to temperature, gene dose, and sex. Mutant (but not wild-type) proinsulin expression in the eye imaginal disc induces IRE1-mediated XBP1 alternative splicing, a signal for endoplasmic reticulum stress response activation, and produces global change in gene expression. Mutant hINS transgene tester strains, when crossed to stocks from the Drosophila Genetic Reference Panel, produce F1 adults with a continuous range of disease phenotypes and large broad-sense heritability. Surprisingly, the severity of mutant hINS-induced disease in the eye is not correlated with that in the notum in these crosses, nor with eye reduction phenotypes caused by the expression of two dominant eye mutants acting in two different eye development pathways, Drop (Dr) or Lobe (L), when crossed into the same genetic backgrounds. The tissue specificity of genetic variability for mutant hINS-induced disease has, therefore, its own distinct signature. The genetic dominance of disease-specific phenotypic variability in our model of misfolded human proinsulin makes this approach amenable to genome-wide association study in a simple F1 screen of natural variation.<\/jats:p>","DOI":"10.1534\/genetics.113.157602","type":"journal-article","created":{"date-parts":[[2013,11,27]],"date-time":"2013-11-27T03:08:42Z","timestamp":1385521722000},"page":"539-555","source":"Crossref","is-referenced-by-count":25,"title":["Genetic Complexity in a<i>Drosophila<\/i>Model of Diabetes-Associated Misfolded Human Proinsulin"],"prefix":"10.1093","volume":"196","author":[{"given":"Soo-Young","family":"Park","sequence":"first","affiliation":[{"name":"Department of Medicine , University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael Z","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolution , University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia A","family":"Tamarina","sequence":"additional","affiliation":[{"name":"Department of Medicine , University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin Z","family":"He","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolution , University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah H","family":"Carl","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolution , University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desiree A","family":"Dickerson","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolution , University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Levi","family":"Barse","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolution , University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bharath","family":"Arun","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolution , University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calvin L","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolution , University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecelia M","family":"Miles","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolution , University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis H","family":"Philipson","sequence":"additional","affiliation":[{"name":"Department of Medicine , University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald F","family":"Steiner","sequence":"additional","affiliation":[{"name":"Department of Medicine , University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme I","family":"Bell","sequence":"additional","affiliation":[{"name":"Department of Medicine , University of Chicago, Chicago, Illinois 60637"},{"name":"Department of Human Genetics , University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Kreitman","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolution , University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,2,1]]},"reference":[{"key":"2023042007210312800_bib1","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1038\/ng.332","article-title":"Systems genetics of complex traits in Drosophila melanogaster.","volume":"41","author":"Ayroles","year":"2009","journal-title":"Nat. Genet."},{"key":"2023042007210312800_bib2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1101\/gad.11.1.1","article-title":"Mouse models of human disease. Part I: techniques and resources for genetic analysis in mice.","volume":"11","author":"Bedell","year":"1997","journal-title":"Genes Dev."},{"key":"2023042007210312800_bib3","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1101\/gad.11.1.11","article-title":"Mouse models of human disease. Part II: recent progress and future directions.","volume":"11","author":"Bedell","year":"1997","journal-title":"Genes Dev."},{"key":"2023042007210312800_bib4","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/282525a0","article-title":"Nucleotide sequence of a cDNA clone encoding human preproinsulin.","volume":"282","author":"Bell","year":"1979","journal-title":"Nature"},{"key":"2023042007210312800_bib5","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J Roy. Statist. Soc. Ser. B"},{"key":"2023042007210312800_bib6","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1534\/genetics.108.088906","article-title":"Quantitative trait loci affecting phenotypic plasticity and the allometric relationship of ovariole number and thorax length in Drosophila melanogaster.","volume":"180","author":"Bergland","year":"2008","journal-title":"Genetics"},{"key":"2023042007210312800_bib7","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1146\/annurev.genet.39.110304.095804","article-title":"Drosophila as a model for human neurodegenerative disease.","volume":"39","author":"Bilen","year":"2005","journal-title":"Annu. Rev. Genet."},{"key":"2023042007210312800_bib8","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1371\/journal.pgen.0030177","article-title":"Genome-wide screen for modifiers of ataxin-3 neurodegeneration in Drosophila.","volume":"3","author":"Bilen","year":"2007","journal-title":"PLoS Genet."},{"key":"2023042007210312800_bib9","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.exger.2010.11.003","article-title":"Regulation of Drosophila lifespan by JNK signaling.","volume":"46","author":"Biteau","year":"2011","journal-title":"Exp. Gerontol."},{"key":"2023042007210312800_bib10","unstructured":"Carl, S. H., 2010\u2003Naturally occurring genetic variation influences the severity of Drosophila eye degeneration induced by expression of a mutant human insulin gene. Undergraduate Thesis, University of Chicago, Chicago."},{"key":"2023042007210312800_bib11","doi-asserted-by":"crossref","first-page":"10338","DOI":"10.1523\/JNEUROSCI.19-23-10338.1999","article-title":"Analysis of the role of heat shock protein (Hsp) molecular chaperones in polyglutamine disease.","volume":"19","author":"Chai","year":"1999","journal-title":"J. Neurosci."},{"key":"2023042007210312800_bib12","first-page":"241","article-title":"Drosophila models of polyglutamine diseases.","volume":"217","author":"Chan","year":"2003","journal-title":"Methods Mol. Biol."},{"key":"2023042007210312800_bib13","doi-asserted-by":"crossref","first-page":"2811","DOI":"10.1093\/hmg\/9.19.2811","article-title":"Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila.","volume":"9","author":"Chan","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"2023042007210312800_bib14","doi-asserted-by":"crossref","first-page":"4005","DOI":"10.1242\/dev.129.17.4005","article-title":"Lobe mediates Notch signaling to control domain-specific growth in the Drosophila eye disc.","volume":"129","author":"Chern","year":"2002","journal-title":"Development"},{"key":"2023042007210312800_bib15","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1038\/ng2049","article-title":"Using FlyAtlas to identify better Drosophila melanogaster models of human disease.","volume":"39","author":"Chintapalli","year":"2007","journal-title":"Nat. Genet."},{"key":"2023042007210312800_bib16","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/S0092-8674(00)81360-4","article-title":"A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response.","volume":"87","author":"Cox","year":"1996","journal-title":"Cell"},{"key":"2023042007210312800_bib17","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1534\/genetics.105.053868","article-title":"Epidermal growth factor receptor and transforming growth factor-beta signaling contributes to variation for wing shape in Drosophila melanogaster.","volume":"173","author":"Dworkin","year":"2006","journal-title":"Genetics"},{"key":"2023042007210312800_bib18","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1534\/genetics.108.096453","article-title":"Genomic consequences of background effects on scalloped mutant expressivity in the wing of Drosophila melanogaster.","volume":"181","author":"Dworkin","year":"2009","journal-title":"Genetics"},{"key":"2023042007210312800_bib19","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/S0092-8674(00)81385-9","article-title":"Reiterative use of the EGF receptor triggers differentiation of all cell types in the Drosophila eye.","volume":"87","author":"Freeman","year":"1996","journal-title":"Cell"},{"key":"2023042007210312800_bib20","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/s004270050291","article-title":"Snail-type zinc finger proteins prevent neurogenesis in Scutoid and transgenic animals of Drosophila.","volume":"209","author":"Fuse","year":"1999","journal-title":"Dev. Genes Evol."},{"key":"2023042007210312800_bib21","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1242\/dev.029645","article-title":"Drosophila dosage compensation: a complex voyage to the X chromosome.","volume":"136","author":"Gelbart","year":"2009","journal-title":"Development"},{"key":"2023042007210312800_bib22","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.cmet.2009.08.002","article-title":"Remote control of insulin secretion by fat cells in Drosophila.","volume":"10","author":"Geminard","year":"2009","journal-title":"Cell Metab."},{"key":"2023042007210312800_bib23","doi-asserted-by":"crossref","first-page":"R989","DOI":"10.1016\/j.cub.2008.08.011","article-title":"Cryptic genetic variation.","volume":"18","author":"Gibson","year":"2008","journal-title":"Curr. Biol."},{"key":"2023042007210312800_bib24","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1126\/science.1124514","article-title":"Progressive disruption of cellular protein folding in models of polyglutamine diseases.","volume":"311","author":"Gidalevitz","year":"2006","journal-title":"Science"},{"key":"2023042007210312800_bib25","doi-asserted-by":"crossref","first-page":"e1000399","DOI":"10.1371\/journal.pgen.1000399","article-title":"Destabilizing protein polymorphisms in the genetic background direct phenotypic expression of mutant SOD1 toxicity.","volume":"5","author":"Gidalevitz","year":"2009","journal-title":"PLoS Genet."},{"key":"2023042007210312800_bib26","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1002\/jez.b.21299","article-title":"Association of orthodenticle with natural variation for early embryonic patterning in Drosophila melanogaster.","volume":"312","author":"Goering","year":"2009","journal-title":"J. Exp. Zool. B Mol. Dev. Evol."},{"key":"2023042007210312800_bib27","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.1101\/gad.1343705","article-title":"Global regulation of X chromosomal genes by the MSL complex in Drosophila melanogaster.","volume":"19","author":"Hamada","year":"2005","journal-title":"Genes Dev."},{"key":"2023042007210312800_bib28","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/1471-2121-11-59","article-title":"Endoplasmic reticulum stress response in an INS-1 pancreatic beta-cell line with inducible expression of a folding-deficient proinsulin.","volume":"11","author":"Hartley","year":"2010","journal-title":"BMC Cell Biol."},{"key":"2023042007210312800_bib29","doi-asserted-by":"crossref","first-page":"523","DOI":"10.18632\/aging.100185","article-title":"Adult Drosophila melanogaster as a model for the study of glucose homeostasis.","volume":"2","author":"Haselton","year":"2010","journal-title":"Aging"},{"key":"2023042007210312800_bib30","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1534\/genetics.113.157800","article-title":"Effect of genetic variation in a Drosophila model of diabetes-associated misfolded human proinsulin.","volume":"196","author":"He","year":"2014","journal-title":"Genetics"},{"key":"2023042007210312800_bib32","doi-asserted-by":"crossref","first-page":"15553","DOI":"10.1073\/pnas.1213423109","article-title":"Epistasis dominates the genetic architecture of Drosophila quantitative traits.","volume":"109","author":"Huang","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023042007210312800_bib33","doi-asserted-by":"crossref","first-page":"17043","DOI":"10.1073\/pnas.0905566106","article-title":"Suppression of retinal degeneration in Drosophila by stimulation of ER-associated degradation.","volume":"106","author":"Kang","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023042007210312800_bib34","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/ncb2447","article-title":"CDK5 and MEKK1 mediate pro-apoptotic signalling following endoplasmic reticulum stress in an autosomal dominant retinitis pigmentosa model.","volume":"14","author":"Kang","year":"2012","journal-title":"Nat. Cell Biol."},{"key":"2023042007210312800_bib35","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.tem.2008.11.004","article-title":"Insulin and JNK: optimizing metabolic homeostasis and lifespan.","volume":"20","author":"Karpac","year":"2009","journal-title":"Trends Endocrinol. Metab."},{"key":"2023042007210312800_bib81","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1172\/JCI1842","article-title":"Mapping of murine diabetogenic gene mody on chromosome 7 at D7Mit258 and its involvement in pancreatic islet and beta cell development during the perinatal period","volume":"101","author":"Kayo","year":"1998","journal-title":"J Clin Invest"},{"key":"2023042007210312800_bib36","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1101\/gr.134031.111","article-title":"Genetic dissection of a model complex trait using the Drosophila synthetic population resource.","volume":"22","author":"King","year":"2012","journal-title":"Genome Res."},{"key":"2023042007210312800_bib37","doi-asserted-by":"crossref","first-page":"e29","DOI":"10.1371\/journal.pbio.0060029","article-title":"Polyglutamine genes interact to modulate the severity and progression of neurodegeneration in Drosophila.","volume":"6","author":"Lessing","year":"2008","journal-title":"PLoS Biol."},{"key":"2023042007210312800_bib38","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/nrg2563","article-title":"Maintaining the brain: insight into human neurodegeneration from Drosophila melanogaster mutants.","volume":"10","author":"Lessing","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"2023042007210312800_bib39","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1038\/nature06909","article-title":"RNA toxicity is a component of ataxin-3 degeneration in Drosophila.","volume":"453","author":"Li","year":"2008","journal-title":"Nature"},{"key":"2023042007210312800_bib40","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/nrg2091","article-title":"Animal models of human disease: zebrafish swim into view.","volume":"8","author":"Lieschke","year":"2007","journal-title":"Nat. Rev. Genet."},{"key":"2023042007210312800_bib41","doi-asserted-by":"crossref","first-page":"e13333","DOI":"10.1371\/journal.pone.0013333","article-title":"Mutant INS-gene induced diabetes of youth: proinsulin cysteine residues impose dominant-negative inhibition on wild-type proinsulin transport.","volume":"5","author":"Liu","year":"2010","journal-title":"PLoS ONE"},{"key":"2023042007210312800_bib42","doi-asserted-by":"crossref","first-page":"6233","DOI":"10.1073\/pnas.90.13.6233","article-title":"Localization of sequences controlling the spatial, temporal, and sex-specific expression of the esterase 6 locus in Drosophila melanogaster adults.","volume":"90","author":"Ludwig","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023042007210312800_bib43","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1098\/rstb.2009.0315","article-title":"Mutations and quantitative genetic variation: lessons from Drosophila.","volume":"365","author":"Mackay","year":"2010","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"2023042007210312800_bib44","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1038\/ng1210-1033","article-title":"Evolutionary genetics quantified.","volume":"42","author":"Mackay","year":"2011","journal-title":"Nat. Genet."},{"key":"2023042007210312800_bib45","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/nrg2612","article-title":"The genetics of quantitative traits: challenges and prospects.","volume":"10","author":"Mackay","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"2023042007210312800_bib46","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/nature10811","article-title":"The Drosophila melanogaster genetic reference panel.","volume":"482","author":"Mackay","year":"2012","journal-title":"Nature"},{"key":"2023042007210312800_bib47","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1038\/emboj.2009.76","article-title":"ER stress protects from retinal degeneration.","volume":"28","author":"Mendes","year":"2009","journal-title":"EMBO J."},{"key":"2023042007210312800_bib48","doi-asserted-by":"crossref","first-page":"4660","DOI":"10.1073\/pnas.050010197","article-title":"mRNA splicing-mediated C-terminal replacement of transcription factor Hac1p is required for efficient activation of the unfolded protein response.","volume":"97","author":"Mori","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023042007210312800_bib49","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1006\/dbio.2001.0229","article-title":"Dominant Drop mutants are gain-of-function alleles of the muscle segment homeobox gene (msh) whose overexpression leads to the arrest of eye development.","volume":"233","author":"Mozer","year":"2001","journal-title":"Dev. Biol."},{"key":"2023042007210312800_bib50","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1146\/annurev.cellbio.24.110707.175242","article-title":"Mechanisms of growth and homeostasis in the Drosophila wing.","volume":"25","author":"Neto-Silva","year":"2009","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"2023042007210312800_bib51","doi-asserted-by":"crossref","first-page":"e601","DOI":"10.1371\/journal.pone.0000601","article-title":"Genetic variation for cardiac dysfunction in Drosophila.","volume":"2","author":"Ocorr","year":"2007","journal-title":"PLoS ONE"},{"key":"2023042007210312800_bib52","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1172\/JCI0214550","article-title":"Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes.","volume":"109","author":"Oyadomari","year":"2002","journal-title":"J. Clin. Invest."},{"key":"2023042007210312800_bib53","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1534\/genetics.103.021766","article-title":"Association between nucleotide variation in Egfr and wing shape in Drosophila melanogaster.","volume":"167","author":"Palsson","year":"2004","journal-title":"Genetics"},{"key":"2023042007210312800_bib54","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1124\/pr.110.003293","article-title":"Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery.","volume":"63","author":"Pandey","year":"2011","journal-title":"Pharmacol. Rev."},{"key":"2023042007210312800_bib55","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1016\/j.bbrc.2009.12.090","article-title":"Mutant proinsulin proteins associated with neonatal diabetes are retained in the endoplasmic reticulum and not efficiently secreted.","volume":"391","author":"Park","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2023042007210312800_bib56","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.peptides.2012.05.003","article-title":"Therapeutic peptide production in Drosophila.","volume":"36","author":"Park","year":"2012","journal-title":"Peptides"},{"key":"2023042007210312800_bib57","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/ng1944","article-title":"Quantitative trait transcripts for nicotine resistance in Drosophila melanogaster.","volume":"39","author":"Passador-Gurgel","year":"2007","journal-title":"Nat. Genet."},{"key":"2023042007210312800_bib58","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1002\/neu.480220503","article-title":"Characterization and spatial distribution of the ELAV protein during Drosophila melanogaster development.","volume":"22","author":"Robinow","year":"1991","journal-title":"J. Neurobiol."},{"key":"2023042007210312800_bib59","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1002\/dvdy.22771","article-title":"Drosophila cancer models.","volume":"241","author":"Rudrapatna","year":"2012","journal-title":"Dev. Dyn."},{"key":"2023042007210312800_bib60","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1038\/sj.emboj.7601477","article-title":"Unfolded protein response in a Drosophila model for retinal degeneration.","volume":"26","author":"Ryoo","year":"2007","journal-title":"EMBO J."},{"key":"2023042007210312800_bib61","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1210\/er.2007-0039","article-title":"The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes.","volume":"29","author":"Scheuner","year":"2008","journal-title":"Endocr. Rev."},{"key":"2023042007210312800_bib62","doi-asserted-by":"crossref","first-page":"e199","DOI":"10.1371\/journal.pgen.0030199","article-title":"Lessons from \u201clower\u201d organisms: what worms, flies, and zebrafish can teach us about human energy metabolism.","volume":"3","author":"Schlegel","year":"2007","journal-title":"PLoS Genet."},{"key":"2023042007210312800_bib63","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/S0092-8674(01)00612-2","article-title":"Complementary signaling pathways regulate the unfolded protein response and are required for C. elegans development.","volume":"107","author":"Shen","year":"2001","journal-title":"Cell"},{"key":"2023042007210312800_bib64","doi-asserted-by":"crossref","first-page":"3378","DOI":"10.1172\/JCI34587","article-title":"Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes.","volume":"118","author":"Song","year":"2008","journal-title":"J. Clin. Invest."},{"key":"2023042007210312800_bib65","doi-asserted-by":"crossref","first-page":"10824","DOI":"10.1073\/pnas.92.24.10824","article-title":"Gene disruptions using P transposable elements: an integral component of the Drosophila genome project.","volume":"92","author":"Spradling","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023042007210312800_bib66","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/nrg751","article-title":"The art and design of genetic screens: Drosophila melanogaster.","volume":"3","author":"St. Johnston","year":"2002","journal-title":"Nat. Rev. Genet."},{"key":"2023042007210312800_bib67","doi-asserted-by":"crossref","first-page":"15040","DOI":"10.1073\/pnas.0707291104","article-title":"Insulin gene mutations as a cause of permanent neonatal diabetes.","volume":"104","author":"Stoy","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023042007210312800_bib68","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s11154-010-9151-3","article-title":"Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene.","volume":"11","author":"Stoy","year":"2010","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"2023042007210312800_bib69","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/ncb0311-184","article-title":"Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress.","volume":"13","author":"Tabas","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"2023042007210312800_bib71","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s10709-005-8549-4","article-title":"Genetic architecture of two fitness-related traits in Drosophila melanogaster: ovariole number and thorax length.","volume":"125","author":"Telonis-Scott","year":"2005","journal-title":"Genetica"},{"key":"2023042007210312800_bib72","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1534\/genetics.112.139337","article-title":"Investigating natural variation in Drosophila courtship song by the evolve and resequence approach.","volume":"191","author":"Turner","year":"2012","journal-title":"Genetics"},{"key":"2023042007210312800_bib73","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1172\/JCI4431","article-title":"A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta-cell dysfunction in the Mody mouse.","volume":"103","author":"Wang","year":"1999","journal-title":"J. Clin. Invest."},{"key":"2023042007210312800_bib74","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1038\/oby.2005.232","article-title":"Quantitative trait loci for lipid content in Drosophila melanogaster.","volume":"13","author":"Wang","year":"2005","journal-title":"Obes. Res."},{"key":"2023042007210312800_bib75","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1093\/jhered\/esl009","article-title":"A quantitative trait locus analysis of natural genetic variation for Drosophila melanogaster oxidative stress survival.","volume":"97","author":"Wang","year":"2006","journal-title":"J. Hered."},{"key":"2023042007210312800_bib76","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.mod.2009.08.005","article-title":"Reduction of Lobe leads to TORC1 hypoactivation that induces ectopic Jak\/STAT signaling to impair Drosophila eye development.","volume":"126","author":"Wang","year":"2009","journal-title":"Mech. Dev."},{"key":"2023042007210312800_bib77","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/70532","article-title":"Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70.","volume":"23","author":"Warrick","year":"1999","journal-title":"Nat. Genet."},{"key":"2023042007210312800_bib78","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.molcel.2005.02.030","article-title":"Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanism.","volume":"18","author":"Warrick","year":"2005","journal-title":"Mol. Cell"},{"key":"2023042007210312800_bib79","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/S0092-8674(01)00611-0","article-title":"XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor.","volume":"107","author":"Yoshida","year":"2001","journal-title":"Cell"},{"key":"2023042007210312800_bib80","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/B978-0-12-387003-2.00008-2","article-title":"Modeling human trinucleotide repeat diseases in Drosophila.","volume":"99","author":"Yu","year":"2011","journal-title":"Int. Rev. Neurobiol."}],"container-title":["Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/genetics\/article-pdf\/196\/2\/539\/50037988\/genetics0539.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/genetics\/article-pdf\/196\/2\/539\/50037988\/genetics0539.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,20]],"date-time":"2024-05-20T14:41:23Z","timestamp":1716216083000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/genetics\/article\/196\/2\/539\/5935577"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,2,1]]},"references-count":79,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2014,2,1]]},"published-print":{"date-parts":[[2014,2,1]]}},"URL":"https:\/\/doi.org\/10.1534\/genetics.113.157602","relation":{},"ISSN":["1943-2631"],"issn-type":[{"value":"1943-2631","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2014,2,1]]},"published":{"date-parts":[[2014,2,1]]}}}