Export file:


  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text


  • Citation Only
  • Citation and Abstract

Non-autonomous consequences of cell death and other perks of being metazoan

Department of Molecular, Cellular and Developmental Biology, 347 UCB, University of Colorado, Boulder, CO 80309-0347, USA

Special Issues: Drosophila models of tumourigenesis

Drosophila melanogaster remains a foremost genetic model to study basic cell biological processes in the context of multi-cellular development. In such context, the behavior of one cell can influence another. Non-autonomous signaling among cells occurs throughout metazoan development and disease, and is too vast to be covered by a single review. I will focus here on non-autonomous signaling events that occur in response to cell death in the larval epithelia and affect the life-death decision of surviving cells. I will summarize the use of Drosophila to study cell death-induced proliferation, apoptosis-induced apoptosis, and apoptosis-induced survival signaling. Key insights from Drosophila will be discussed in the context of analogous processes in mammalian development and cancer biology.
  Article Metrics

Keywords Drosophila; imaginal discs; apoptosis; caspase; cancer

Citation: Tin Tin Su. Non-autonomous consequences of cell death and other perks of being metazoan. AIMS Genetics, 2015, 2(1): 54-69. doi: 10.3934/genet.2015.1.54


  • 1. Haynie JL, Bryant PJ (1977) The Effects of X-rays on the Proliferation Dynamics of Cels in the Imaginal Wing Disc of Drosophila melanogaster. Wilhelm Roux's Archives 183: 85-100.    
  • 2. James AA, Bryant PJ (1981) A quantitative study of cell death and mitotic inhibition in gamma-irradiated imaginal wing discs of Drosophila melanogaster. Radiat Res 87: 552-564.    
  • 3. Milan M, Campuzano S, Garcia-Bellido A (1997) Developmental parameters of cell death in the wing disc of Drosophila. P Natl Acad Sci USA 94: 5691-5696.    
  • 4. Meier P, Silke J, Leevers SJ, et al. (2000) The Drosophila caspase DRONC is regulated by DIAP1. EMBO J 19: 598-611.    
  • 5. Mollereau B, Perez-Garijo A, Bergmann A, et al. (2013) Compensatory proliferation and apoptosis-induced proliferation: a need for clarification. Cell Death Differ 20: 181.    
  • 6. Martin FA, Perez-Garijo A, Morata G (2009) Apoptosis in Drosophila: compensatory proliferation and undead cells. Int J Dev Biol 53: 1341-1347.    
  • 7. Perez-Garijo A, Martin FA, Morata G (2004) Caspase inhibition during apoptosis causes abnormal signalling and developmental aberrations in Drosophila. Development 131: 5591-5598.    
  • 8. Ryoo HD, Gorenc T, Steller H (2004) Apoptotic cells can induce compensatory cell proliferation through the JNK and the Wingless signaling pathways. Dev Cell 7: 491-501.    
  • 9. Callus BA, Vaux DL (2007) Caspase inhibitors: viral, cellular and chemical. Cell Death Differ 14: 73-78.    
  • 10. Hadley C (2003) What doesn't kill you makes you stronger. A new model for risk assessment may not only revolutionize the field of toxicology, but also have vast implications for risk assessment. EMBO Rep 4: 924-926.
  • 11. Miyachi Y (2000) Acute mild hypothermia caused by a low dose of X-irradiation induces a protective effect against mid-lethal doses of X-rays, and a low level concentration of ozone may act as a radiomimetic. Brit J Radiol 73: 298-304.    
  • 12. Kondo S (1988) Altruistic cell suicide in relation to radiation hormesis. Int J Radiat Biol Relat Stud Phys Chem Med 53: 95-102.    
  • 13. Huh JR, Guo M, Hay BA (2004) Compensatory proliferation induced by cell death in the Drosophila wing disc requires activity of the apical cell death caspase Dronc in a nonapoptotic role. Curr Biol 14: 1262-1266.    
  • 14. McEwen DG, Peifer M (2005) Puckered, a Drosophila MAPK phosphatase, ensures cell viability by antagonizing JNK-induced apoptosis. Development 132: 3935-3946.    
  • 15. Garcia-Bellido A, Ripoll P, Morata G (1973) Developmental compartmentalisation of the wing disk of Drosophila. Nat New Biol 245: 251-253.
  • 16. Perez-Garijo A, Shlevkov E, Morata G (2009) The role of Dpp and Wg in compensatory proliferation and in the formation of hyperplastic overgrowths caused by apoptotic cells in the Drosophila wing disc. Development 136: 1169-1177.    
  • 17. Martin-Blanco E, Gampel A, Ring J, et al. (1998) puckered encodes a phosphatase that mediates a feedback loop regulating JNK activity during dorsal closure in Drosophila. Gene Dev 12: 557-570.    
  • 18. Fan Y, Bergmann A (2008) Distinct mechanisms of apoptosis-induced compensatory proliferation in proliferating and differentiating tissues in the Drosophila eye. Dev Cell 14: 399-410.    
  • 19. Kondo S, Senoo-Matsuda N, Hiromi Y, et al. (2006) DRONC coordinates cell death and compensatory proliferation. Mol Cell Biol 26: 7258-7268.    
  • 20. Wichmann A, Jaklevic B, Su TT (2006) Ionizing radiation induces caspase-dependent but Chk2- and p53-independent cell death in Drosophila melanogaster. P Natl Acad Sci USA 103: 9952-9957.    
  • 21. Wells BS, Johnston LA (2012) Maintenance of imaginal disc plasticity and regenerative potential in Drosophila by p53. Dev Biol 361: 263-276.    
  • 22. Wells BS, Yoshida E, Johnston LA (2006) Compensatory proliferation in Drosophila imaginal discs requires Dronc-dependent p53 activity. Curr Biol 16: 1606-1615.    
  • 23. Dichtel-Danjoy ML, Ma D, Dourlen P, et al. (2013) Drosophila p53 isoforms differentially regulate apoptosis and apoptosis-induced proliferation. Cell Death Differ 20: 108-116.    
  • 24. Wylie A, Lu WJ, D'Brot A, et al. (2014) p53 activity is selectively licensed in the Drosophila stem cell compartment. eLife 3: e01530.
  • 25. Shlevkov E, Morata G (2012) A dp53/JNK-dependant feedback amplification loop is essential for the apoptotic response to stress in Drosophila. Cell Death Differ 19: 451-460.    
  • 26. Lee TV, Fan Y, Wang S, et al. (2011) Drosophila IAP1-mediated ubiquitylation controls activation of the initiator caspase DRONC independent of protein degradation. PLoS Genet 7: e1002261.    
  • 27. Martin FA, Herrera SC, Morata G (2009) Cell competition, growth and size control in the Drosophila wing imaginal disc. Development 136: 3747-3756.    
  • 28. Fan Y, Wang S, Hernandez J, et al. (2014) Genetic models of apoptosis-induced proliferation decipher activation of JNK and identify a requirement of EGFR signaling for tissue regenerative responses in Drosophila. PLoS Genet 10: e1004131.    
  • 29. Schubiger M, Sustar A, Schubiger G (2010) Regeneration and transdetermination: the role of wingless and its regulation. Dev Biol 347: 315-324.    
  • 30. Smith-Bolton RK, Worley MI, Kanda H, et al. (2009) Regenerative growth in Drosophila imaginal discs is regulated by Wingless and Myc. Dev Cell 16: 797-809.    
  • 31. Staley BK, Irvine KD (2012) Hippo signaling in Drosophila: recent advances and insights. Dev Dyn 241: 3-15.    
  • 32. Yu FX, Guan KL (2013) The Hippo pathway: regulators and regulations. Gene Dev 27: 355-371.    
  • 33. Grusche FA, Degoutin JL, Richardson HE, et al. (2011) The Salvador/Warts/Hippo pathway controls regenerative tissue growth in Drosophila melanogaster. Dev Biol 350: 255-266.    
  • 34. Sun G, Irvine KD (2011) Regulation of Hippo signaling by Jun kinase signaling during compensatory cell proliferation and regeneration, and in neoplastic tumors. Dev Biol 350: 139-151.    
  • 35. Grusche FA, Richardson HE, Harvey KF (2010) Upstream regulation of the hippo size control pathway. Curr Biol 20: R574-582.    
  • 36. Wu M, Pastor-Pareja JC, Xu T (2010) Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion. Nature 463: 545-548.    
  • 37. Jezowska B, Fernandez BG, Amandio AR, et al. (2011) A dual function of Drosophila capping protein on DE-cadherin maintains epithelial integrity and prevents JNK-mediated apoptosis. Dev Biol 360: 143-159.    
  • 38. Kagey JD, Brown JA, Moberg KH (2012) Regulation of Yorkie activity in Drosophila imaginal discs by the Hedgehog receptor gene patched. Mech Develop 129: 339-349.    
  • 39. Christiansen AE, Ding T, Fan Y, et al. (2013) Non-cell autonomous control of apoptosis by ligand-independent Hedgehog signaling in Drosophila. Cell Death Differ 20: 302-311.    
  • 40. Christiansen AE, Ding T, Bergmann A (2012) Ligand-independent activation of the Hedgehog pathway displays non-cell autonomous proliferation during eye development in Drosophila. Mech Develop 129: 98-108.    
  • 41. Herrera SC, Martin R, Morata G (2013) Tissue homeostasis in the wing disc of Drosophila melanogaster: immediate response to massive damage during development. PLoS Genet 9: e1003446.    
  • 42. Bergantinos C, Corominas M, Serras F (2010) Cell death-induced regeneration in wing imaginal discs requires JNK signalling. Development 137: 1169-1179.    
  • 43. Li F, Huang Q, Chen J, et al. (2010) Apoptotic cells activate the ""phoenix rising"" pathway to promote wound healing and tissue regeneration. Sci Signal 3: ra13.
  • 44. Li X, Wang Z, Ma Q, et al. (2014) Sonic hedgehog paracrine signaling activates stromal cells to promote perineural invasion in pancreatic cancer. Clin Cancer Res 20: 4326-4338.    
  • 45. Huang Q, Li F, Liu X, et al. (2011) Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat Med 17: 860-866.    
  • 46. Sun Y, Campisi J, Higano C, et al. (2012) Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med 18: 1359-1368.    
  • 47. Perez-Garijo A, Fuchs Y, Steller H (2013) Apoptotic cells can induce non-autonomous apoptosis through the TNF pathway. eLife 2: e01004.
  • 48. Bilak A, Uyetake L, Su TT (2014) Dying cells protect survivors from radiation-induced cell death in Drosophila. PLoS Genet 10: e1004220.    
  • 49. Brennecke J, Hipfner DR, Stark A, et al. (2003) bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113: 25-36.    
  • 50. Mothersill C, Seymour C (2006) Radiation-induced bystander effects: evidence for an adaptive response to low dose exposures? Dose Response 4: 283-290.    
  • 51. Mothersill C, Seymour CB (2006) Radiation-induced bystander effects and the DNA paradigm: an ""out of field"" perspective. Mutat Res 597: 5-10.    
  • 52. Mothersill C, Stamato TD, Perez ML, et al. (2000) Involvement of energy metabolism in the production of 'bystander effects' by radiation. Brit J Cancer 82: 1740-1746.    
  • 53. Singh H, Saroya R, Smith R, et al. (2011) Radiation induced bystander effects in mice given low doses of radiation in vivo. Dose Response 9: 225-242.    
  • 54. van Deursen JM (2014) The role of senescent cells in ageing. Nature 509: 439-446.    
  • 55. Rodgers JT, King KY, Brett JO, et al. (2014) mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert). Nature 510: 393-396.
  • 56. Taylor RC, Berendzen KM, Dillin A (2014) Systemic stress signalling: understanding the cell non-autonomous control of proteostasis. Nat Rev Mol Cell Bio 15: 211-217.    


This article has been cited by

  • 1. Helena E. Richardson, Drosophila models of cancer, AIMS Genetics, 2015, 2, 1, 97, 10.3934/genet.2015.1.97
  • 2. Shilpi Verghese, Tin Tin Su, Bruce A Edgar, Drosophila Wnt and STAT Define Apoptosis-Resistant Epithelial Cells for Tissue Regeneration after Irradiation, PLOS Biology, 2016, 14, 9, e1002536, 10.1371/journal.pbio.1002536
  • 3. J Manent, S Banerjee, R de Matos Simoes, T Zoranovic, C Mitsiades, J M Penninger, K J Simpson, P O Humbert, H E Richardson, Autophagy suppresses Ras-driven epithelial tumourigenesis by limiting the accumulation of reactive oxygen species, Oncogene, 2017, 10.1038/onc.2017.175
  • 4. Helena E. Richardson, Marta Portela, Modelling Cooperative Tumorigenesis in Drosophila, BioMed Research International, 2018, 2018, 1, 10.1155/2018/4258387

Reader Comments

your name: *   your email: *  

Copyright Info: 2015, Tin Tin Su, licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Copyright © AIMS Press All Rights Reserved