title: A steroid-controlled global switch in sensitivity to apoptosis during Drosophila development.
abstract: Precise control over activation of the apoptotic machinery is critical for development, tissue homeostasis and disease. In Drosophila, the decision to trigger apoptosis--whether in response to developmental cues or to DNA damage--converges on transcription of inhibitor of apoptosis protein (IAP) antagonists reaper, hid and grim. Here we describe a parallel process that regulates the sensitivity to, rather than the execution of, apoptosis. This process establishes developmental windows that are permissive or restrictive for triggering apoptosis, where the status of cells determines their capacity to die. We characterize one switch in the sensitivity to apoptotic triggers, from restrictive to permissive, that occurs during third-instar larval (L3) development. Early L3 animals are highly resistant to induction of apoptosis by expression of IAP-antagonists, DNA-damaging agents and even knockdown of the IAP diap1. This resistance to apoptosis, however, is lost in wandering L3 animals after acquiring a heightened sensitivity to apoptotic triggers. This switch in sensitivity to death activators is mediated by a change in mechanisms available for activating endogenous caspases, from an apoptosome-independent to an apoptosome-dependent pathway. This switch in apoptotic pathways is regulated in a cell-autonomous manner by the steroid hormone ecdysone, through changes in expression of critical pro-, but not anti-, apoptotic genes. This steroid-controlled switch defines a novel, physiologically-regulated, mechanism for controlling sensitivity to apoptosis and provides new insights into the control of apoptosis during development.
authors: Division of Pharmaceutical Sciences, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705-2222, USA; Laboratory of Genetics Graduate Program, University of Wisconsin-Madison, Madison, WI, USA.
authors: Yunsik
authors: Y
authors: Kang
authors: Division of Pharmaceutical Sciences, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705-2222, USA; Laboratory of Genetics Graduate Program, University of Wisconsin-Madison, Madison, WI, USA. Electronic address: bashirullah@wisc.edu.
authors: Arash
authors: A
authors: Bashirullah
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D003433:Crosses, Genetic; D004330:Drosophila / Q000196:embryology*; D029721:Drosophila Proteins / Q000378:metabolism*; D004440:Ecdysone / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D015398:Signal Transduction; D013256:Steroids / Q000378:metabolism; D013696:Temperature; D013997:Time Factors; D019076:Transgenes
chemical_list: C111891:DIAP1 protein, Drosophila; D029721:Drosophila Proteins; D051034:Inhibitor of Apoptosis Proteins; D013256:Steroids; D049452:Green Fluorescent Proteins; D004440:Ecdysone; D020169:Caspases
keywords: Apoptosis; Apoptosome-dependent; Apoptosome-independent; Ecdysone; Sensitivity to apoptosis; mid-L3 transition