An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control
Open accessAbstract
Background Size regulation is fundamental in developing multicellular organisms and occurs through the control of cell number and cell size. Studies in Drosophila have identified an evolutionarily conserved signaling pathway that regulates organismal size and that includes the Drosophila insulin receptor substrate homolog Chico, the lipid kinase PI(3)K (Dp110), DAkt1/dPKB, and dS6K.Results We demonstrate that varying the activity of the Drosophila insulin receptor homolog (DInr) during development regulates organ size by changing cell size and cell number in a cell-autonomous manner. An amino acid substitution at the corresponding position in the kinase domain of the human and Drosophila insulin receptors causes severe growth retardation. Furthermore, we show that the Drosophila genome contains seven insulin-like genes that are expressed in a highly tissue- and stage-specific pattern. Overexpression of one of these insulin-like genes alters growth control in a DInr-dependent manner.Conclusions This study shows that the Drosophila insulin receptor autonomously controls cell and organ size, and that overexpression of a gene encoding an insulin-like peptide is sufficient to increase body size.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Insulin-like peptides likely have ancient internal-coordination roles in growth and physiology.
“have probably ancient IC roles in the regulation of growth, as well as physiology (see above) [85,87].”
From An option space for early neural evolution (2015) · cites this paper as [87]
Cites
Targeted gene expression as a means of altering cell fates and generating dominant phenotypes
Brand, A. H., & Perrimon, N. (1993) · Development · doi:10.1242/dev.118.2.401 · Cited by 9,510 · see citing works
The Genome Sequence of Drosophila melanogaster
Adams, M. D., Celniker, S., Holt, R. A., Evans, C. A., Gocayne, J. D., Amanatides, P. G., Scherer, S. E., Li, P. W., Hoskins, R. A., Galle, R. F., et al. (2000) · Science · doi:10.1126/science.287.5461.2185 · Cited by 5,902 · see citing works
Identification of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites
Nielsen, H., Engelbrecht, J., Brunak, S., & von HEIJNE, G. (1997) · Protein Engineering Design and Selection · doi:10.1093/protein/10.1.1 · Cited by 5,324 · see citing works
Prediction of complete gene structures in human genomic DNA
Burge, C., & Karlin, S. (1997) · Journal of Molecular Biology · doi:10.1006/jmbi.1997.0951 · Cited by 4,211 · see citing works
Analysis of genetic mosaics in developing and adult Drosophila tissues
Xu, T., & Rubin, G. M. (1993) · Development · doi:10.1242/dev.117.4.1223 · Cited by 2,067 · see citing works
The human insulin receptor cDNA: The structural basis for hormone-activated transmembrane signalling
Ebina, Y., Ellis, L., Jarnagin, K., Edery, M., Gráf, L., Clauser, É., Ou, J. J., Masiarz, F. R., Kan, Y. W., Goldfine, I. D., et al. (1985) · Cell · doi:10.1016/0092-8674(85)90334-4 · Cited by 1,477 · see citing works
CRYSTAL STRUCTURE OF THE TYROSINE KINASE DOMAIN OF THE HUMAN INSULIN RECEPTOR
Hubbard, S. R., Wei, L., Ellis, L., & Hendrickson, W. A. (1994) · Nature · doi:10.1038/372746a0 · Cited by 1,080 · see citing works
Expression of baculovirus P35 prevents cell death in Drosophila
Hay, B. A., Wolff, T., & Rubin, G. M. (1994) · Development · doi:10.1242/dev.120.8.2121 · Cited by 1,066 · see citing works
Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1-4.
Böhni, R., Riesgo-Escovar, J., Oldham, S., Brogiolo, W., Stocker, H., Andruss, B., Beckingham, K., & Hafen, E. (1999) · Cell · doi:10.1016/s0092-8674(00)80799-0 · Cited by 863 · see citing works
Self-citationDrosophila S6 kinase: a regulator of cell size.
Montagne, J., Stewart, M. J., Stocker, H., Hafen, E., Kozma, S., & Thomas, G. (1999) · Science · doi:10.1126/science.285.5436.2126 · Cited by 785 · see citing works
Self-citationSize Control in Animal Development
Conlon, I. J., & RAFF, M. C. (1999) · Cell · doi:10.1016/s0092-8674(00)80563-2 · Cited by 743 · see citing works
Azpiazu, N., & Frasch, M. (1993) · Genes & Development · doi:10.1101/gad.7.7b.1325 · Cited by 724 · see citing works
Analysis of Drosophila photoreceptor axon guidance in eye-specific mosaics
Newsome, T. P., Åsling, B., & Dickson, B. J. (2000) · Development · doi:10.1242/dev.127.4.851 · Cited by 630 · see citing works
The Drosophila phosphoinositide 3‐kinase Dp110 promotes cell growth.
Leevers, S. J., Weinkove, D., MacDougall, L. K., Hafen, E., & Waterfield, M. D. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb01049.x · Cited by 487 · see citing works
Self-citationBritton, J. S., & Edgar, B. A. (1998) · Development · doi:10.1242/dev.125.11.2149 · Cited by 476 · see citing works
Clinical features and natural history of Beckwith‐Wiedemann syndrome: presentation of 74 new cases
Elliott, M. M., Bayly, R. J., Cole, T., Temple, I. K., & Maher, E. R. (1994) · Clinical Genetics · doi:10.1111/j.1399-0004.1994.tb04219.x · Cited by 423 · see citing works
Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB
Verdú, J., Buratovich, M., Wilder, E., & Birnbaum, M. (1999) · Nature Cell Biology · doi:10.1038/70293 · Cited by 397 · see citing works
Halder, G. A., Callaerts, P., Flister, S., Walldorf, U., Kloter, U., & Gehring, W. J. (1998) · Development · doi:10.1242/dev.125.12.2181 · Cited by 391 · see citing works
Partridge, L., Barrie, B., Fowler, K., & French, V. (1994) · Evolution · doi:10.1111/j.1558-5646.1994.tb05311.x · Cited by 381 · see citing works
Hormone families: pancreatic hormones and homologous growth factors
Blundell, T. L., & HUMBEL, R. E. (1980) · Nature · doi:10.1038/287781a0 · Cited by 378 · see citing works
Goberdhan, D. C. I., Paricio, N., Goodman, E. C., Mlodzik, M., & Wilson, C. (1999) · Genes & Development · doi:10.1101/gad.13.24.3244 · Cited by 355 · see citing works
Efstratiadis, A. (1998) · The International Journal of Developmental Biology · doi:10.1387/ijdb.9853827 · Cited by 349 · see citing works
Fernandez, R. J., Tabarini, D., Azpiazu, N., Frasch, M., & Schlessinger, J. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb07343.x · Cited by 341 · see citing works
Self-citationThe Drosophila insulin receptor is required for normal growth.
Chen, C., Jack, J., & Garofalo, R. S. (1996) · Endocrinology · doi:10.1210/endo.137.3.8603594 · Cited by 338 · see citing works
The developmental basis for allometry in insects
Stern, D. L., & Emlen, D. J. (1999) · Development · doi:10.1242/dev.126.6.1091 · Cited by 323 · see citing works
PTEN affects cell size, cell proliferation and apoptosis during Drosophila eye development
Huang, H., Potter, C. J., Tao, W., Li, D., Brogiolo, W., Hafen, E., Sun, H., & Xu, T. (1999) · Development · doi:10.1242/dev.126.23.5365 · Cited by 321 · see citing works
Self-citationWeinkove, D., Neufeld, T. P., Twardzik, T., Waterfield, M. D., & Leevers, S. J. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80450-3 · Cited by 293 · see citing works
Growth-controlling molluscan neurons produce the precursor of an insulin-related peptide
Smit, A. B., Vreugdenhil, E., EBBERINK, R. H. M., et al. (1988) · Nature · doi:10.1038/331535a0 · Cited by 292 · see citing works
Gaul, U., Mardon, G., & Rubin, G. M. (1992) · Cell · doi:10.1016/0092-8674(92)90073-l · Cited by 278 · see citing works
Eukaryotic protein processing: endoproteolysis of precursor proteins
Seidah, N. G., & Chrétien, M. (1997) · Current Opinion in Biotechnology · doi:10.1016/s0958-1669(97)80036-5 · Cited by 270 · see citing works
Gao, X., Neufeld, T. P., & Pan, D. (2000) · Developmental Biology · doi:10.1006/dbio.2000.9680 · Cited by 260 · see citing works
Partridge, L., Barrie, B., Fowler, K., & French, V. (1994) · Evolution · doi:10.2307/2410384 · Cited by 187 · see citing works
Double-label in situ hybridization using biotin and digoxigenin-tagged RNA probes.
O’Neill, J., & Bier, E. (1994) · PubMed · Cited by 156 · see citing works
Duret, L., Guex, N., Peitsch, M. C., et al. (1998) · Genome Research · doi:10.1101/gr.8.4.348 · Cited by 152 · see citing works
Glucose Stimulates the Release of Bombyxin, an Insulin-Related Peptide of the Silkworm Bombyx mori
Masumura, M., Satake, S., Saegusa, H., et al. (2000) · General and Comparative Endocrinology · doi:10.1006/gcen.1999.7438 · Cited by 143 · see citing works
Robertson, F. W. (1959) · Genetics · doi:10.1093/genetics/44.5.869 · Cited by 127 · see citing works
Yenush, L., Fernandez, R. J., Myers, M. G., et al. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.5.2509 · Cited by 89 · see citing works
Self-citationKawakami, A., Iwami, M., Nagasawa, H. T., et al. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.18.6843 · Cited by 88 · see citing works
Breschi, M., Seghieri, G., Bartolomei, G., Gironi, A., Baldi, S., & Ferrannini, E. (1993) · Diabetologia · doi:10.1007/bf00400812 · Cited by 79 · see citing works
In situ hybridization to RNA in plant tissue
Meyerowitz, E. M. (1987) · Plant Molecular Biology Reporter · doi:10.1007/bf02669719 · Cited by 74 · see citing works
Hétru, C., Li, K. W., Bulet, P., Lagueux, M., & Hoffmann, J. A. (1991) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1991.tb16308.x · Cited by 73 · see citing works
A homozygous kinase-defective mutation in the insulin receptor gene in a patient with leprechaunism
Takahashi, Y., Kadowaki, H., Momomura, K., Fukushima, Y., Orban, T., Okai, T., Taketani, Y., Akanuma, Y., Yazaki, Y., & Kadowaki, T. (1997) · Diabetologia · doi:10.1007/s001250050695 · Cited by 70 · see citing works
Luschnig, S., Krauß, J., Bohmann, K., et al. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)80419-0 · Cited by 65 · see citing works
Menon, R. K., & Sperling, M. A. (1996) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/s0889-8529(05)70344-3 · Cited by 59 · see citing works
Pancreatic Development and Maturation of the Islet B Cell
Madsen, O. D., Jensen, J. N., Blume, N., Petersen, H. V., Lund, K., Karlsen, C., Andersen, F. G., Jensen, P. B., Larsson, L., & Serup, P. (1996) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1996.435rr.x · Cited by 55 · see citing works
Lehmann, R., & Tautz, D. (1994) · MPG.PuRe (Max Planck Society) · Cited by 46 · see citing works
Milner, R. D. G. (1996) · Archives of Disease in Childhood · doi:10.1136/adc.74.5.369 · Cited by 22 · see citing works
Molecular mechanisms of inherited insulin resistance
Baynes, K., Whitehead, J. P., Krook, A., & O’Rahilly, S. (1997) · QJM · doi:10.1093/qjmed/90.9.557 · Cited by 19 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Insulin and insulin-like growth factor signalling in neoplasia
Pollak, M. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2536 · Cited by 2,059 · see citing works
Ablation of Insulin-Producing Neurons in Flies: Growth and Diabetic Phenotypes
Rulifson, E. J., Kim, S. K., & Nusse, R. (2002) · Science · doi:10.1126/science.1070058 · Cited by 1,064 · see citing works
A Single-Cell Transcriptome Atlas of the Aging Drosophila Brain
Davie, K., Janssens, J., Koldere, D., De Waegeneer, M., Pech, U., Kreft, Ł., Aibar, S., Makhzami, S., Christiaens, V., Bravo González-Blas, C., et al. (2018) · Cell · doi:10.1016/j.cell.2018.05.057 · Cited by 840 · see citing works
Broughton, S. J., Piper, M. D. W., Ikeya, T., Bass, T. M., Jacobson, J., Driege, Y., Martinez, P., Hafen, E., Withers, D. J., Leevers, S. J., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0405775102 · Cited by 822 · see citing works
Self-citationA nutrient sensor mechanism controls Drosophila growth
Colombani, J., Raisin, S., Pantalacci, S., Radimerski, T., Montagne, J., & Léopold, P. (2003) · Cell · doi:10.1016/s0092-8674(03)00713-x · Cited by 809 · see citing works
Insulin-like growth factor signaling in fish
Wood, A. W., Duan, C., & Bern, H. A. (2005) · International Review of Cytology · doi:10.1016/s0074-7696(05)43004-1 · Cited by 657 · see citing works
A Mechanism of Extreme Growth and Reliable Signaling in Sexually Selected Ornaments and Weapons
Emlen, D. J., Warren, I. A., Johns, A., Dworkin, I., & Lavine, L. C. (2012) · Science · doi:10.1126/science.1224286 · Cited by 454 · see citing works
Finch, C. E., & Ruvkun, G. (2001) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.2.1.435 · Cited by 446 · see citing works
Cellular diversity in the Drosophila midbrain revealed by single-cell transcriptomics
Croset, V., Treiber, C. D., & Waddell, S. (2018) · eLife · doi:10.7554/elife.34550 · Cited by 299 · see citing works
Insulin/IGF-like signalling, the central nervous system and aging
Broughton, S., & Partridge, L. (2009) · Biochemical Journal · doi:10.1042/bj20082102 · Cited by 228 · see citing works
Stiles, B., Groszer, M., Wang, S., Jiao, J., & Wu, H. (2004) · Developmental Biology · doi:10.1016/j.ydbio.2004.06.008 · Cited by 230 · see citing works
Primary cilia and coordination of receptor tyrosine kinase (RTK) signalling
Christensen, S. T., Clement, C. A., Satir, P., & Pedersen, L. B. (2012) · The Journal of Pathology · doi:10.1002/path.3004 · Cited by 181 · see citing works
Buch, S., Melcher, C., Bauer, M., Katzenberger, J., & Pankratz, M. J. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.02.012 · Cited by 179 · see citing works
An option space for early neural evolution
Jékely, G., Keijzer, F., & Godfrey-Smith, P. (2015) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2015.0181 · Cited by 171 · see citing works
Kapan, N., Lushchak, O. V., Luo, J., & Nässel, D. R. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1097-z · Cited by 169 · see citing works
A causal role for hyperinsulinemia in obesity
Templeman, N. M., Skovsø, S., Page, M. M., Lim, G. E., & Johnson, J. D. (2017) · Journal of Endocrinology · doi:10.1530/joe-16-0449 · Cited by 168 · see citing works
Ecdysone signaling underlies the pea aphid transgenerational wing polyphenism
Vellichirammal, N. N., Gupta, P., Hall, T. A., & Brisson, J. A. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1617640114 · Cited by 154 · see citing works
Systemic corazonin signalling modulates stress responses and metabolism in<i>Drosophila</i>
Kubrak, O. I., Lushchak, O. V., Zandawala, M., & Nässel, D. R. (2016) · Open Biology · doi:10.1098/rsob.160152 · Cited by 134 · see citing works
Regulation of ecdysone production in <i>Drosophila</i> by neuropeptides and peptide hormones
Kannangara, J. R., Mirth, C. K., & Warr, C. G. (2021) · Open Biology · doi:10.1098/rsob.200373 · Cited by 84 · see citing works
Rhea, J. M., Wegener, C., & Bender, M. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1000967 · Cited by 48 · see citing works
- Authors
- Brogiolo, W., Stocker, H., Ikeya, T., Rintelen, F., Fernandez, R., & Hafen, E.
- Affiliations
- University of Zurich (CH)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Hafen, Ernst
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2001-02
- Volume
- 11
- Issue
- 4
- Pages
- 213-221
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W2083850113
- Cited by
- 1,255
- References
- 48
- Citations by year
- 2026: 35 · 2025: 49 · 2024: 41 · 2023: 45 · 2022: 58 · 2021: 69 · 2020: 68 · 2019: 57 · 2018: 77 · 2017: 45 · 2016: 45 · 2015: 53 · 2014: 53 · 2013: 63 · 2012: 48
- FWCI
- 13.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
- Keywords
- insulin receptor, insulin-like peptides, organ size control, cell size, cell number, growth regulation, Chico, phosphatidylinositol 3-kinase, AKT1, S6K, Drosophila development, growth retardation, tissue-specific gene expression
- MeSH terms
- Amino Acid Sequence, Amino Acids, Animals, Binding Sites, Cell Count, Cell Division, Drosophila, Gene Expression Regulation, Humans, Insulin, Molecular Sequence Data, Peptides, Receptor, Insulin, Gene Expression, Mutagenesis, Conserved Sequence, Genes, Insect, Receptor, IGF Type 1, Evolution, Molecular, Insect Proteins, Receptor Protein-Tyrosine Kinases, Animals, Genetically Modified, Cell Size
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
