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Examination of Niddm20 candidate genes of OLETF rats in Drosophila melanogaster using inducible GeneSwitch GAL4 system

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Abstract

Type 2 diabetes mellitus (T2D) is a metabolic disorder caused by a complex interplay between genetic and environmental factors. While remarkable progress have been made in our understanding of the genetic components that lead to disease expression, the ‘diabetes genes’ identified to date are inadequate for assessing disease risk, which suggests that many other genes remain to be discovered. Here, we used Drosophila to examine the protein-coding genes annotated in the hyperglycaemic locus of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a well-characterized model of T2D. We identified lilliputian (lilli), a fly homolog of AF4/FMR2 family member 2, as a novel candidate gene for T2D. Lilli knockdown adult females had significantly higher haemolymph trehalose and glucose levels, while dilp2, which plays a major role in sugar metabolism, was downregulated. Tissue-specific knockdown strain revealed that lilli plays a crucial function in oenocytes and the fat body, which together are homologous organs to the liver. Together, these findings demonstrate the importance of using fly models for investigating polygenic diseases such as T2D.

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References

  • Akhi M., Kose H. and Matsumoto K. 2005 Fine mapping of the hyperglycemic and obesity QTL by congenic strains suggests multiple loci on rat chromosome 14. J. Med. Invest. 52, 109–113.

    Article  Google Scholar 

  • Alfa R. W. and Kim S. K. 2016 Using Drosophila to discover mechanisms underlying type 2 diabetes. Dis. Model. Mech. 9, 365–376.

    Article  CAS  Google Scholar 

  • Bai H., Ping K. and Marc T. 2012 Drosophila insulin-like peptide-6 (dilp6) expression from fat body extends lifespan and represses secretion of Drosophila insulin-like peptide-2 from the brain. Aging Cell 11, 978–985.

    Article  CAS  Google Scholar 

  • Broughton S., Alic N., Slack C., Bass T., Ikeya T., Vinti G. et al. 2008 Reduction of DILP2 in Drosophila triages a metabolic phenotype from lifespan revealing redundancy and compensation among DILPs. PLoS One 3, 3–11.

    Article  Google Scholar 

  • Broughton S. J., Piper M. D., Ikeya T., Bass T. M., Jacobson J., Driege Y. et al. 2005 Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands. Proc. Natl. Acad. Sci. USA 102, 3105–3110.

    Article  CAS  Google Scholar 

  • Chatterjee D., Katewa S. D., Qi Y., Jackson S. A., Kapahi P. and Jasper H. 2014 Control of metabolic adaptation to fasting by dILP6-induced insulin signaling in Drosophila oenocytes. Proc. Natl. Acad. Sci. USA 111, 17959–17964.

    Article  CAS  Google Scholar 

  • Colombani J., Andersen D. S. and Léopol P. 2012 Secreted peptide dilp8 coordinates Drosophila tissue growth with developmental timing. Science 336, 582–585.

    Article  CAS  Google Scholar 

  • Deng A. Y. 2015 Genetic mechanisms of polygenic hypertension: fundamental insights from experimental models. J. Hypertens 33, 669–680.

    Article  CAS  Google Scholar 

  • Grönke S., Clarke D. F., Broughton S., Andrews T. D. and Partridge L. 2010 Molecular evolution and functional characterization of Drosophila insulin-like peptides. PLoS Genet. 6 (https://doi.org/10.1371/journal.pgen.1000857).

  • Gutierrez E., Wiggins D., Fielding B. and Gould A. P. 2007 Specialized hepatocyte-like cells regulate Drosophila lipid metabolism. Nature 445, 275–280.

    Article  CAS  Google Scholar 

  • Gu Y. and Nelson D. L. 2003 FMR2 Function: insight from a mouse knockout model. Cytogenet. Genome Res. 100, 129–139.

    Article  CAS  Google Scholar 

  • Haselton A., Sharmin E., Schrader J., Sah M., Poon P. and Fridell Y. W. 2010 Partial ablation of adult Drosophila insulin-producing neurons modulates glucose homeostasis and extends life span without insulin resistance. Cell Cycle 9, 3063–3071.

    Article  CAS  Google Scholar 

  • Haselton A. T. and Fridell Y. W. 2011 Insulin injection and hemolymph extraction to measure insulin sensitivity in adult Drosophila melanogaster. J. vis. Exp. 52, 2–5.

    Google Scholar 

  • Hayashi S., Ito K., Sado Y., Taniguchi M., Akimoto A., Takeuchi H. et al. 2002 GETDB, a database compiling expression patterns and molecular locations of a collection of Gal4 enhancer traps. Genesis 34, 58–61.

    Article  CAS  Google Scholar 

  • Hwangbo D. S., Garsham B., Tu M. P., Palmer M. and Tatar M. 2004 Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 429, 562–566.

    Article  CAS  Google Scholar 

  • Ikeya T., Galic M., Belawat P., Nairz K. and Hafen E. 2002 Nutrient-dependent expression of insulin-like peptides from neuroendocrine cells in the CNS contributes to growth regulation in Drosophila. Curr. Biol. 12, 1293–1300.

    Article  CAS  Google Scholar 

  • Kawano K., Hirashima T., Mori S. and Natori T. 1994 OLETF (Otsuka Long-Evans Tokushima Fatty) rat: a new NIDDM rat strain. Diabetes Res. Clin. Pract. 24, S317–S320.

    Article  Google Scholar 

  • Kawano K., Mori S., Hirashima T., Man Z. W. and Natori T. 1999 Examination of the pathogenesis of diabetic nephropathy in OLETF rats. J. Vet. Med. Sci. 61, 1219–1228.

    Article  CAS  Google Scholar 

  • Kawasaki K. Yamada S., Ogata K., Saito Y., Takahama A., Yamada T. et al. 2015 Use of Drosophila as an evaluation method reveals imp as a candidate gene for type 2 diabetes in rat locus Niddm22. J. Diabetes. Res. (https://doi.org/10.1155/2015/758564).

  • Klowden M. J. 2008 Physiological systems in insects, Academic Press, London.

    Google Scholar 

  • Kose H., Band Y., Izumi K., Yamada T. and Matsumoto K. 2007 Epistasis between hyperglycemic QTLs revealed in a double congenic of the OLETF rat. Mamm. Genome 18, 609–615.

    Article  Google Scholar 

  • Kose H., Moralejo D. H., Ogino T., Mizuno A., Yamada T. and Matsumoto K. 2002 Examination of OLETF-derived non-insulin-dependent diabetes mellitus QTL by construction of a series of congenic rats. Mamm. Genome 13, 558–562.

    Article  CAS  Google Scholar 

  • Lee J. H., Lee J. H. and Rane S. G. R. 2021 TGF-β signaling in pancreatic islet β cell development and function. Endocrinology 162, 1–10.

    Google Scholar 

  • Ma X., Cui Z., Du Z. and Lin H. 2020 Transforming growth factor-β signaling, a potential mechanism associated with diabetes mellitus and pancreatic cancer? J. Cell. Physiol. 235, 5882–5892.

    Article  CAS  Google Scholar 

  • Melicharek D., Shah A., DiStefano G., Gangemi A. J., Orapallo A., Vrailas-Mortimer A. D. et al. 2008 Identification of novel regulators of atonal expression in the developing Drosophila retina. Genetics 180, 2095–2110.

    Article  CAS  Google Scholar 

  • Melko M., Douguet D., Bensaid M., Zongaro S., Gecz J. and Bardoni B. 2011 Functional characterization of the AFF (AF4/FMR2) family of RNA-binding proteins: insights into the molecular pathology of FRAXE intellectual disability. Hum. Mol. Genet. 20, 1873–1885.

    Article  CAS  Google Scholar 

  • Moralejo D. H., Wei S., Wei K., Weksler-Zangen S., Koike G., Jacob H. J. et al. 1998 Identification of quantitative trait loci for non-insulin-dependent diabetes mellitus that interact with body weight in the Otsuka Long-Evans Tokushima Fatty rat. Proc. Assoc. Am. Physicians 110, 545–558.

    CAS  PubMed  Google Scholar 

  • Nicholson L., Singh G. K., Osterwalder T., Roman G. W., Davis R. L. and Keshishian H. 2008 Spatial and temporal control of gene expression in Drosophila using the inducible GeneSwitch GAL4 System. I. Screen for larval nervous system drivers. Genetics 178, 215–234.

    Article  CAS  Google Scholar 

  • Ogino T., Wei S., Wei K., Moralejo D. H., Kose H., Mizuno A. et al. 2000 Genetic evidence for obesity loci involved in the regulation of body fat distribution in obese type 2 diabetes rat, OLETF. BMC Genom. 70, 19–25.

    Article  CAS  Google Scholar 

  • Okamoto N., Nakamori R., Mura T., Yamauch Y., Masuda A. and Nishimura T. 2013 A secreted decoy of InR antagonizes insulin/IGF signaling to restrict body growth in Drosophila. Genes Dev 27, 87–97.

    Article  CAS  Google Scholar 

  • Pendse J., Ramachandran P. V., Na J., Narisu N., Fink J. L., Cagan R. L. et al. 2013 A Drosophila functional evaluation of candidates from human genome-wide association studies of type 2 diabetes and related metabolic traits identifies tissue-specific roles for dHHEX. BMC Genomics 14 (https://doi.org/10.1186/1471-2164-14-136).

  • Pospisilik J. A., Schramek D., Schnidar H., Croni S. J., Nehme N. T., Zhang X. et al. 2010 Drosophila genome-wide obesity screen reveals hedgehog as a determinant of brown versus white adipose cell fate. Cell 140, 148–160.

    Article  CAS  Google Scholar 

  • Rogulja D. and Irvine K. D. 2005 Regulation of cell proliferation by a morphogen gradient. Cell 123, 449–461.

    Article  CAS  Google Scholar 

  • Rulifson E. J., Kim S. K. and Nusse R. 2002 Ablation of insulin-producing neurons in files: Growth and diabetic phenotypes. Science 296, 1118–1120.

    Article  CAS  Google Scholar 

  • Sekine O., Love D. C., Rubenstein D. S. and Hanover J. A. 2010 Blocking O-linked GlcNAc cycling in Drosophila insulin-producing cells perturbs glucose-insulin homeostasis. J. Biol. Chem. 285, 38684–38691.

    Article  CAS  Google Scholar 

  • Stančáková A. and Markku L. 2016 Genetics of type 2 diabetes. Endocr. Dev. 31, 203–220.

    Article  Google Scholar 

  • Su M. A., Wisotzkey R. G. and Newfeld S. J. 2001 A screen for modifiers of decapentaplegic mutant phenotypes identifies lilliputian, the only member of the Fragile-X/Burkitt’s Lymphoma family of transcription factors in Drosophila melanogaster. Genetics 157, 717–725.

    Article  CAS  Google Scholar 

  • Tang A. H., Neufeld T. P., Rubin G. M. and Müller H. J. 2001 Transcriptional regulation of cytoskeletal functions and segmentation by a novel maternal pair-rule gene, lilliputian. Development 813, 801–813.

    Article  Google Scholar 

  • Ugrankar R., Berglund E., Akdemir F., Tran C., Kim M. S., Noh J. et al. 2015 Drosophila glucome screening identifies Ck1alpha as a regulator of mammalian glucose metabolism. Nat. Commun. 6, 1–10.

    Article  Google Scholar 

  • Wittwer F., van der Straten A., Keleman K., Dickson B. J. and Hafen E. 2001 Lilliputian: An AF4/FMR2-related protein that controls cell identity and cell growth. Development 128, 791–800.

    Article  CAS  Google Scholar 

  • Yadav H., Quijano C., Kamaraju A. K., Gavrilova O., Malek R., Chen W. et al. 2011 Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling. Cell Metab. 14, 67–79.

    Article  CAS  Google Scholar 

  • Yuva-Aydemir Y., Almeida S., Krishnan G., Gendron T. F. and Gao F. B. 2019 Transcription elongation factor AFF2/FMR2 regulates expression of expanded GGGGCC repeat-containing C9ORF72 allele in ALS/FTD. Nat. Commun. 10 (https://doi.org/10.1038/s41467-019-13477-8).

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Acknowledgements

The authors thank KYOTO Stock Center (DGRC) at Kyoto Institute of Technology, the Vienna Drosophila RNAi Center, and the National Institute of Genetics (NIG) for fly stocks.

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Author notes

  1. Yuto Moronuki

    Present address: Laboratory of Bio-Resource Regulation, Department of Integrated BioSciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba, 277-0882, Japan

Authors and Affiliations

  1. Department of Natural Sciences, International Christian University, Mitaka, Tokyo, 181-8585, Japan

    Lan Enli, Yuto Moronuki & Hiroyuki Kose

  2. Faculty of Agriculture, Department of Agrobiology, Niigata University, Nishi-ku, Niigata, 950-2181, Japan

    Takahisa Yamada

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  1. Lan Enli
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  2. Yuto Moronuki
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  3. Takahisa Yamada
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  4. Hiroyuki Kose
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Correspondence to Hiroyuki Kose.

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Corresponding editor: Rohit Joshi

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Enli, L., Moronuki, Y., Yamada, T. et al. Examination of Niddm20 candidate genes of OLETF rats in Drosophila melanogaster using inducible GeneSwitch GAL4 system. J Genet 101, 15 (2022). https://doi.org/10.1007/s12041-021-01356-5

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  • DOI: https://doi.org/10.1007/s12041-021-01356-5

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