Abstract
Steroid hormones play an important role in the regulation of numerous physiological responses, but the mechanisms that enable these systemic signals to trigger specific cell changes remain poorly characterized. Recent studies of Drosophila illustrate several important features of steroid-regulated programmed cell death. A single steroid hormone activates both cell differentiation and cell death in different tissues and at multiple stages during development. While several steroid-regulated genes are required for cell execution, most of these genes function in both cell differentiation and cell death, and require more specific factors to kill cells. Genes that regulate apoptosis during Drosophila embryogenesis are induced by steroids in dying cells later in development. These apoptosis genes likely function downstream of hormone-induced factors to serve a more direct role in the death response. This article reviews the current knowledge of steroid signaling and the regulation of programmed cell death during development of Drosophila. Cell Death and Differentiation (2000) 7, 1057–1062
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Thompson CB . 1995 Apoptosis in the pathogenesis and treatment of disease. Science 267: 1456–1462
Briehl MM and Miesfeld RL . 1991 Isolation and characterization of transcripts induced by androgen withdrawal and apoptotic cell death in the rat ventral prostate. Mol. Endocrinol. 5: 1381–1388
Rotello RJ, Lieberman RC, Lepoff RB and Gerschenson LE . 1992 Characterization of uterine epithelium apoptotic cell death kinetics and regulation by progesterone and RU 486. Am. J. Pathol. 140: 449–456
Tenniswood MP, Guenette RS, Lakins J, Mooibroek M, Wong P and Welsh J-E . 1992 Active cell death in hormone-dependent tissues. Cancer Metastasis Rev. 11: 197–220
Billig H, Furata I and Hsueh AJW . 1993 Estrogens inhibit and androgens enhance ovarian granulosa cell apoptosis. Endocrinology 133: 2204–2212
Compton MM and Cidlowski JA . 1986 Rapid in vivo effects of glucocorticoids on the integrity of rat lymphocyte genomic deoxyribonucleic acid. Endocrinology 118: 38–45
Dieken ES and Miesfeld RL . 1992 Transcriptional transactivation functions localized to the glucocorticoid receptor N terminus are necessary for steroid induction of lymphocyte apoptosis. Mol. Cell. Biol. 12: 589–597
Helmberg A, Auphan N, Caelles C and Karin M . 1995 Glucocorticoid-induced apoptosis of human leukemic cells is caused by the repressive function of the glucocorticoid receptor. EMBO J. 14: 452–460
Cohen JJ and Duke RC . 1984 Glucocorticoid activation of a calcium-dependent endonucleasein thymocyte nuclei leads to cell death. J. Immunol. 132: 38–42
Wyllie AH . 1980 Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284: 555–556
Lockshin RA and Williams CM . 1964 Programmed cell death-II. Endocrine potentiation of the breakdown of the intersegmental muscles of silkmoths. J. Insect Physiol. 10: 643–649
Lockshin RA and Williams CM . 1965 Programmed cell death-I. Cytology of degeneration in the intersegmental muscles of the pernyi silkmoth. J. Insect Physiol. 11: 123–133
Robinow S, Talbot WS, Hogness DS and Truman JW . 1993 Programmed cell death in the Drosophila CNS is ecdysone-regulated and coupled with a specific ecdysone receptor isoform. Development 119: 1251–1259
Truman JW, Talbot WS, Fahrbach SE and Hogness DS . 1994 Ecdysone receptor expression in the CNS correlates with stage-specific responses to ecdysteroids during Drosophila and Manduca development. Development 120: 219–234
Isaacs JT . 1984 Antagonistic effect of androgen on prostatic cell death. Prostate 5: 545–557
Jiang C, Baehrecke EH and Thummel CT . 1997 Steroid regulated programmed cell death during Drosophila metamorphosis. Development 124: 4673–4683
Vacchio MS, Lee JYM and Ashwell JD . 1999 Thymus-derived glucocorticoids set the thresholds for thymocyte selection by inhibiting TCR-mediated thymocyte activation. J. Immunol. 163: 1327–1333
Riddiford LM . 1993 Hormones and Drosophila development. In The development of Drosophila melanogaster, Bate M, Martinez Arias A, eds (Cold Spring Harbor: Cold Spring Harbor Laboratory Press) pp. 899–940
Richards G . 1981 The radioimmune assay of ecdysteroid titres in Drosophila melanogaster. Mol. Cell. Endocrinol. 21: 181–197
Handler AM . 1982 Ecdysteroid titres during pupal and adult development in Drosophila melanogaster. Dev. Biol. 93: 73–82
Pak MD and Gilbert LI . 1987 A developmental analysis of ecdysteroids during the metamorphosis of Drosophila melanogaster. J. Liq. Chrom. 10: 2591–2611
Sliter TJ and Gilbert LI . 1992 Developmental arrest and ecdysteroid deficiency resulting from mutations at the dre4 locus of Drosophila. Genetics 130: 555–568
Bodenstein D . 1965 The postembryonic development of Drosophila. In Biology of Drosophila, Demerec M, ed (New York: Hafner Publishing Co.) pp. 275–367
Robertson CW . 1936 The metamorphosis of Drosophila melanogaster, including an accurately timed account of the principal morphological changes. J. Morphol. 59: 351–399
Doctor J, Fristrom D and Fristrom JW . 1985 The pupal cuticle of Drosophila: biphasic synthesis of pupal cuticle proteins in vivo and in vitro in response to 20-hydroxyecdysone. J. Cell Biol. 101: 189–200
von Kalm L, Fristrom D and Fristrom J . 1995 The making of a fly leg: a model for epithelial morphogenesis. BioEssays 17: 693–702
Fristrom D and Fristrom JW . 1993 The metamorphic development of the adult epidermis. In The development of Drosophila melanogaster, Bate M, Martinez Arias A, eds (Cold Spring Harbor: Cold Spring Harbor Laboratory Press) pp. 843–897
Clarke PGH . 1990 Developmental cell death: morphological diversity and multiple mechanisms. Anat. Embryol. 181: 195–213
Schweichel J-U and Merker H-J . 1973 The morphology of various types of cell death in prenatal tissues. Teratology 7: 253–266
Schwartz LM, Smith SW, Jones MEE and Osborne BA . 1993 Do all programmed cell deaths occur via apoptosis? Proc. Natl. Acad. Sci. USA 90: 980–984
Jochova J, Zakeri Z and Lockshin RA . 1997 Rearrangement of the tubulin and actin cytoskeleton during programmed cell death in Drosophila salivary glands. Cell Death Differ. 4: 140–149
von Gaudecker B and Schmale E-M . 1974 Substrate-histochemical investigations and ultrahistochemical demonstrations of acid phosphatase in larval and prepupal salivary glands of Drosophila melanogasater. Cell Tissue Res. 155: 75–89
Ashburner M, Chihara C, Meltzer P and Richards G . 1974 Temporal control of puffing activity in polytene chromosomes. Cold Spring Harbor Symp. Quant. Biol. 38: 655–662
Becker HJ . 1959 Die puffs der speicheldrüsenchromosomen von Drosophila melanogaster. I. Beobachtungen zur verhalten des puffmusters in normalstamm und bei zwei mutanten, giant und lethal-giant-larvae. Chromosoma 10: 654–678
Clever U . 1964 Actinomycin and puromycin: effects on sequential gene activation by ecdysone. Science 146: 794–795
Andres AJ and Thummel CS . 1992 Hormones, puffs, and flies: the molecular control of metamorphosis by ecdysone. Trends Genet. 8: 132–138
Ashburner M . 1990 Puffs, genes, and hormones revisited. Cell 61: 1–3
Koelle MR, Talbot WS, Segraves WA, Bender MT, Cherbas P and Hogness DS . 1991 The Drosophila EcR gene encodes an ecdysone receptor, a new member of the steroid receptor superfamily. Cell 67: 59–77
Henrich VC, Sliter TJ, Lubahn DB, MacIntyre A and Gilbert LI . 1990 A steroid/thyroid hormone receptor superfamily member in Drosophila melanogaster that shares extensive sequence similarity with a mammalian homologue. Nucleic Acids Res. 18: 4143–4148
Oro AE, McKeown M and Evans RM . 1990 Relationship between the product of the Drosophila ultraspiracle locus and vertebrate retinoid X receptor. Nature 347: 298–301
Shea MJ, King DL, Conboy MJ, Mariani BD and Kafatos FC . 1990 Proteins that bind to Drosophila chorion cis-regulatory elements: a new C2H2 zinc finger protein and a C2C2 steroid receptor-like component. Genes Dev. 4: 1128–1140
Thomas HE, Stunnenberg HG and Stewart AF . 1993 Heterodimerization of the Drosophila ecdysone receptor with retinoid X receptor and ultraspiracle. Nature 362: 471–475
Yao T-P, Segraves WA, Oro AE, McKeown M and Evans RM . 1992 Drosophila ultraspiracle modulates ecdysone receptor function via heterodimer formation. Cell 71: 63–72
Bender M, Imam FB, Talbot WS, Ganetzky B and Hogness DS . 1997 Drosophila ecdysone receptor mutations reveal functional differences among receptor isoforms. Cell 91: 777–788
Hall BL and Thummel CS . 1998 The RXR homolog Ultraspiracle is an essential component of the Drosophila ecdysone receptor. Development 125: 4709–4717
Burtis KC, Thummel CS, Jones CW, Karim FD and Hogness DS . 1990 The Drosophila 74EF early puff contains E74, a complex ecdysone-inducible gene that encodes two ets-related proteins. Cell 61: 85–99
DiBello PR, Withers DA, Bayer CA, Fristrom JW and Guild GM . 1991 The Drosophila Broad-Complex encodes a family of related proteins containing zinc fingers. Genetics 129: 385–397
Segraves WA and Hogness DS . 1990 The E75 ecdysone-inducible gene responsible for the 75B early puff in Drosophila encodes two new members of the steroid receptor superfamily. Genes Dev. 4: 204–219
Urness LD and Thummel CS . 1990 Molecular interactions within the ecdysone regulatory hierarchy: DNA binding properties of the Drosophila ecdysone-inducible E74A protein. Cell 63: 47–61
Hill RJ, Segraves WA, Choi D, Underwood PA and Macavoy E . 1993 The reaction with polytene chromosomes of antibodies raised against Drosophila E75 protein. Insect Biochem. Mol. Biol. 23: 99–104
Restifo LL and Guild GM . 1986 An ecdysone-responsive puff site in Drosophila contains a cluster of seven differentially regulated genes. J. Mol. Biol. 188: 517–528
Wright LG, Chen T, Thummel CS and Guild GM . 1996 Molecular characterization of the 71E late puff in Drosophila melanogaster reveals a family of novel genes. J. Mol. Biol. 255: 387–400
Fletcher JC and Thummel CS . 1995 The ecdysone-inducible Broad-Complex and E74 early genes interact to regulate target gene transcription and Drosophila metamorphosis. Genetics 141: 1025–1035
Crossgrove K, Bayer CA, Fristrom JW and Guild GM . 1996 The Drosophila Broad-Complex early gene directly regulates late gene transcription during the ecdysone-induced puffing cascade. Dev. Biol. 180: 745–758
Urness LD and Thummel CS . 1995 Molecular analysis of a steroid-induced regulatory hierarchy: the Drosophila E74A protein directly regulates L71-6 transcription. EMBO J. 14: 6239–6246
von Kalm L, Crossgrove K, Von Seggern D, Guild GM and Beckendorf SK . 1994 The Broad-Complex directly controls a tissue-specific response to the steroid hormone ecdysone at the onset of Drosophila metamorphosis. EMBO J. 13: 3505–3516
Crowley TE and Meyerowitz EM . 1984 Steroid regulation of RNAs transcribed from the Drosophila 68C polytene chromosome puff. Dev. Biol. 102: 110–121
Hansson L and Lambertsson A . 1989 Steroid regulation of glue protein genes in Drosophila melanogaster. Hereditas 110: 61–67
Woodard CT, Baehrecke EH and Thummel CS . 1994 A molecular mechanism for the stage-specificity of the Drosophila prepupal genetic response to ecdysone. Cell 79: 607–615
Broadus J, McCabe JR, Endrizzi B, Thummel CS and Woodard CT . 1999 The Drosophila β FTZ-F1 orphan nuclear receptor provides competence for stage-specific responses to the steroid hormone ecdysone. Mol. Cell 3: 143–149
Ashburner M . 1967 Patterns of puffing activity in the salivary gland chromosomes of Drosophila. I. Autosomal puffing patterns in a laboratory stock of Drosophila melanogaster. Chromosoma 21: 398–428
Jiang C, Lamblin A-FJ, Steller H and Thummel CT . 2000 A steroid-triggered transcriptional hierarchy controls salivary gland cell death during Drosophila metamorphosis. Mol. Cell 5: 445–455
Lee C-Y, Wendel DP, Reid P, Lam G, Thummel CT and Baehrecke EH . 2000 E93 directs steroid-triggered programmed cell death in Drosophila. Mol. Cell: 6: 433–443
Restifo LL and White K . 1992 Mutations in a steroid hormone-regulated gene disrupt the metamorphosis of internal tissues in Drosophila: salivary glands, muscle, and gut. Wilhelm Roux's Arch. Dev. Biol. 201: 221–234
Fletcher JC, Burtis KC, Hogness DS and Thummel CS . 1995 The Drosophila E74 gene is required for metamorphosis and plays a role in the polytene chromosome puffing response to ecdysone. Development 121: 1455–1465
Abrams JM . 1999 An emerging blueprint for apoptosis in Drosophila. Trends Cell Biol. 9: 435–440
Chen P, Rodriguez A, Erskine R, Thach T and Abrams JM . 1998 Dredd, a novel effector of the apoptosis activators Reaper, Grim, and Hid in Drosophila. Dev. Biol. 201: 202–216
Dorstyn L, Colussi PA, Quinn LM, Richardson H and Kumar S . 1999 DRONC, an ecdysone-inducible Drosophila caspase. Proc. Natl. Acad. Sci. USA 96: 4307–4312
Dorstyn L, Read SH, Quinn LM, Richardson H and Kumar S . 1999 DECAY, a novel Drosophila caspase related to mammalian caspase-3 and caspase-7. J. Biol. Chem. 274: 30778–30783
Fraser AG and Evan GI . 1997 Identification of a Drosophila melanogaster ICE/CED-3-relatedprotease, drICE. EMBO J. 16 (10): 2805–2813
Inohara N, Koseki T, Hu Y, Chen S and Nunez G . 1997 CLARP, a death effector domain-containing protein interacts with caspase-8 and regulates apoptosis. Proc. Natl. Acad. Sci. USA 94: 10717–10722
Song Z, McCall K and Steller H . 1997 DCP-1, a Drosophila cell death protease essential for development. Science 275: 536–540
Kanuka H, Sawamoto K, Inohara N, Matsuno K, Okano H and Miura M . 1999 Control of the cell death pathway by Dapaf-1, a Drosophila Apaf-1/CED-4-related caspase activator. Mol. Cell 4: 757–769
Rodriguez A, Oliver H, Zou H, Chen P, Wang X and Abrams JM . 1999 Dark is a Drosophila homologue of Apaf-1/CED-4 and functions in an evolutionarily conserved death pathway. Nat. Cell Biol. 1: 272–279
Zhou L, Song Z, Tittel J and Steller H . 1999 HAC-1, a Drosophila homolog of APAF-1 and CED-4, functions in developmental and radiation-induced apoptosis. Mol. Cell 4: 745–755
Baker Brachmann C, Jassim OW, Wachsmuth BD and Cagan RL . 2000 The Drosophila Bcl-2 family member dBorg-1 functions in the apototic response to UV-irradiation. Curr. Biol. 10: 547–550
Colussi PA, Quinn LM, Huang DCS, Coombe M, Read SH, Richardson H and Kumar S . 2000 Debcl, a proapoptotic Bcl-2 homologue, is a component of the Drosophila melanogaster cell death machinery. J. Cell Biol. 148: 703–714
Igaki T, Kanuka H, Inohara N, Sawamoto K, Nunez G, Okano H and Miura M . 2000 Drob-1, a Drosophila member of the Bcl-2/CED-9 family that promotes cell death. Proc. Natl. Acad. Sci. USA 97: 662–667
Hay BA, Wassarman DA and Rubin GM . 1995 Drosophila homologs of baculovirus inhibitor of apoptosis proteins function to block cell death. Cell 83: 1253–1262
Chen P, Nordstrom W, Gish B and Abrams JM . 1996 grim, a novel cell death gene in Drosophila. Genes Dev. 10: 1773–1782
Grether ME, Abrams JM, Agapite J, White K and Steller H . 1995 The head involution defective gene of Drosophila melanogaster functions in programmed cell death. Genes Dev. 9: 1694–1708
White K, Grether ME, Abrams JM, Young L, Farrell K and Steller H . 1994 Genetic control of programmed cell death in Drosophila. Science 264: 677–683
Robinow S, Draizen TA and Truman JW . 1997 Genes that induce apoptosis: transcriptional regulation in identified, doomed neurons of the Drosophila CNS. Dev. Biol. 190: 206–213
Draizen TA, Ewer J and Robinow S . 1999 Genetic and hormonal regulation of the death of peptidergic neurons in the Drosophila central nervous system. J. Neurobiol. 38: 455–465
Jacobson MD, Weil M and Raff MC . 1997 Programmed cell death in animal development. Cell 88: 347–354
Vaux DL and Korsmeyer SJ . 1999 Cell death in development. Cell 96: 245–254
McCall K and Steller H . 1997 Facing death in the fly: genetic analysis of apoptosis in Drosophila. Trends Genet. 13: 222–226
Goyal L, McCall K, Agapite J, Hartwieg E and Steller H . 2000 Induction of apoptosis by Drosophila reaper, hid and grim through inhibition of IAP function. EMBO J. 19: 589–597
Lisi S, Mazzon I and White K . 2000 Diverse domains of THREAD/DIAP1 are required to inhibit apoptosis induced by REAPER and HID in Drosophila. Genetics 154: 669–678
Wang SL, Hawkins CJ, Yoo SJ, Müller H-AJ and Hay BA . 1999 The Drosophila caspase inhibitor DIAP1 is essential for cell survival and is negatively regulated by HID. Cell 98: 453–463
Acknowledgements
I thank the members of the Baehrecke laboratory for helpful discussions and comments on this manuscript. Work on this subject has been supported by NRICGP/USDA grant 9501913 and NIH grant GM59136.
Author information
Authors and Affiliations
Corresponding author
Additional information
Edited by S Kumar
Rights and permissions
About this article
Cite this article
Baehrecke, E. Steroid regulation of programmed cell death during Drosophila development. Cell Death Differ 7, 1057–1062 (2000). https://doi.org/10.1038/sj.cdd.4400753
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.cdd.4400753
