A collective form of cell death requires homeodomain interacting protein kinase

We examined post-eclosion elimination of the Drosophila wing epithelium in vivo where collective “suicide waves” promote sudden, coordinated death of epithelial sheets without a final engulfment step. Like apoptosis in earlier developmental stages, this unique communal form of cell death is controlled through the apoptosome proteins, Dronc and Dark, together with the IAP antagonists, Reaper, Grim, and Hid. Genetic lesions in these pathways caused intervein epithelial cells to persist, prompting a characteristic late-onset blemishing phenotype throughout the wing blade. We leveraged this phenotype in mosaic animals to discover relevant genes and establish here that homeodomain interacting protein kinase (HIPK) is required for collective death of the wing epithelium. Extra cells also persisted in other tissues, establishing a more generalized requirement for HIPK in the regulation of cell death and cell numbers.

[1]  N. Perrimon,et al.  Autosomal P[ovoD1] dominant female-sterile insertions in Drosophila and their use in generating germ-line chimeras. , 1993, Development.

[2]  Yongsok Kim,et al.  Homeodomain-interacting Protein Kinases, a Novel Family of Co-repressors for Homeodomain Transcription Factors* , 1998, The Journal of Biological Chemistry.

[3]  S. Korsmeyer,et al.  Review Cell Death: Critical Control Points Another Line of Evidence for the Importance of Caspases in Cell Death Came From , 2022 .

[4]  K. Kimura,et al.  Activation of the cAMP/PKA signaling pathway is required for post-ecdysial cell death in wing epidermal cells of Drosophila melanogaster , 2004, Development.

[5]  D. Lindsley,et al.  The Genome of Drosophila Melanogaster , 1992 .

[6]  Antony Rodriguez,et al.  Autophagy occurs upstream or parallel to the apoptosome during histolytic cell death , 2006, Development.

[7]  Antony Rodriguez,et al.  The apical caspase dronc governs programmed and unprogrammed cell death in Drosophila. , 2004, Developmental cell.

[8]  H. Okano,et al.  Reaper-mediated inhibition of DIAP1-induced DTRAF1 degradation results in activation of JNK in Drosophila , 2002, Nature Cell Biology.

[9]  H. Steller,et al.  Genetic control of programmed cell death in Drosophila. , 1994, Science.

[10]  P. Lasko,et al.  Belle is a Drosophila DEAD-box protein required for viability and in the germ line. , 2005, Developmental biology.

[11]  Tian Xu,et al.  Drosophila Atrophin Homolog Functions as a Transcriptional Corepressor in Multiple Developmental Processes , 2002, Cell.

[12]  R A Knight,et al.  Classification of cell death: recommendations of the Nomenclature Committee on Cell Death , 2005, Cell Death and Differentiation.

[13]  M. Paddy,et al.  Tissue remodeling during maturation of the Drosophila wing. , 2007, Developmental biology.

[14]  G. D’Orazi,et al.  HIPK2 inhibits both MDM2 gene and protein by, respectively, p53‐dependent and independent regulations , 2005, FEBS letters.

[15]  T Wolff,et al.  Cell death in normal and rough eye mutants of Drosophila. , 1991, Development.

[16]  John M Abrams,et al.  Caspase activation – stepping on the gas or releasing the brakes? Lessons from humans and flies , 2004, Oncogene.

[17]  Antony Rodriguez,et al.  Dark is a Drosophila homologue of Apaf-1/CED-4 and functions in an evolutionarily conserved death pathway , 1999, Nature Cell Biology.

[18]  A. Bergmann,et al.  ARK, the Apaf-1 related killer in Drosophila, requires diverse domains for its apoptotic activity , 2007, Cell Death and Differentiation.

[19]  A. Wyllie,et al.  Cell death: the significance of apoptosis. , 1980, International review of cytology.

[20]  K. Basler,et al.  A genetic screen for hedgehog targets involved in the maintenance of the Drosophila anteroposterior compartment boundary. , 2003, Genetics.

[21]  S. Hou,et al.  A P-element insertion screen identified mutations in 455 novel essential genes in Drosophila. , 2003, Genetics.

[22]  J. Abrams.  An emerging blueprint for apoptosis in Drosophila. , 1999, Trends in cell biology.

[23]  M. Raff,et al.  Programmed Cell Death in Animal Development , 1997, Cell.

[24]  N. Perrimon,et al.  The autosomal FLP-DFS technique for generating germline mosaics in Drosophila melanogaster. , 1996, Genetics.

[25]  S. Korsmeyer,et al.  Cell Death in Development , 1999, Cell.

[26]  S. Kornbluth,et al.  Apoptosis in Drosophila: neither fish nor fowl (nor man, nor worm) , 2005, Journal of Cell Science.

[27]  M. Bissell,et al.  The extracellular matrix in epithelial biology: shared molecules and common themes in distant phyla. , 1996, Developmental biology.

[28]  Feng Chen,et al.  A complementary transposon tool kit for Drosophila melanogaster using P and piggyBac , 2004, Nature Genetics.

[29]  G. Blandino,et al.  HIPK2 neutralizes MDM2 inhibition rescuing p53 transcriptional activity and apoptotic function , 2004, Oncogene.

[30]  J. Kerr.  Definition and incidence of apoptosis : A historical perspective , 1991 .

[31]  E. Skolnik,et al.  The Drosophila Ste20-related kinase misshapen is required for embryonic dorsal closure and acts through a JNK MAPK module on an evolutionarily conserved signaling pathway. , 1998, Genes & development.

[32]  D. Curtis,et al.  Systematic generation of high-resolution deletion coverage of the Drosophila melanogaster genome , 2004, Nature Genetics.

[33]  Bruce A. Hay,et al.  The Drosophila MicroRNA Mir-14 Suppresses Cell Death and Is Required for Normal Fat Metabolism , 2003, Current Biology.

[34]  M. Milner,et al.  The final stages of wing development in Drosophila melanogaster. , 1987, Tissue & cell.

[35]  C. Rickert,et al.  Programmed cell death in the embryonic central nervous system of Drosophila melanogaster , 2007, Development.

[36]  Scott Barolo,et al.  New Drosophila transgenic reporters: insulated P-element vectors expressing fast-maturing RFP. , 2004, BioTechniques.

[37]  Antony Rodriguez,et al.  Unrestrained caspase‐dependent cell death caused by loss of Diap1 function requires the Drosophila Apaf‐1 homolog, Dark , 2002, The EMBO journal.

[38]  R A Knight,et al.  Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009 , 2005, Cell Death and Differentiation.

[39]  E. Hafen,et al.  Maternal-effect loci involved in Drosophila oogenesis and embryogenesis: P element-induced mutations on the third chromosome. , 2002, The International journal of developmental biology.

[40]  I. Hariharan,et al.  The Drosophila melanogaster Apaf-1 homologue ARK is required for most, but not all, programmed cell death , 2006, The Journal of cell biology.

[41]  Sharad Kumar,et al.  Drosophila caspase DRONC is required for specific developmental cell death pathways and stress-induced apoptosis. , 2004, Developmental cell.

[42]  M. Arcaro,et al.  The CARD-carrying caspase Dronc is essential for most, but not all, developmental cell death in Drosophila , 2005, Development.

[43]  J. Reinitz,et al.  Rapid preparation of a panel of polyclonal antibodies to Drosophila segmentation proteins , 1998, Development Genes and Evolution.

[44]  Giulia Piaggio,et al.  Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis , 2002, Nature Cell Biology.

[45]  A. Wyllie,et al.  Apoptosis: A Basic Biological Phenomenon with Wide-ranging Implications in Tissue Kinetics , 1972, British Journal of Cancer.

[46]  T. Aigaki,et al.  Eiger, a TNF superfamily ligand that triggers the Drosophila JNK pathway , 2002, The EMBO journal.

[47]  Yoichi Taya,et al.  Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2 , 2002, Nature Cell Biology.

[48]  H. Broihier,et al.  Drosophila Homeodomain Protein dHb9 Directs Neuronal Fate via Crossrepressive and Cell-Nonautonomous Mechanisms , 2002, Neuron.

[49]  B. Charroux,et al.  Grunge, related to human Atrophin-like proteins, has multiple functions in Drosophila development. , 2002, Development.

[50]  L. David Tomei,et al.  Apoptosis: The Molecular Basis of Cell Death , 1991 .

[51]  E. Baehrecke,et al.  The Drosophila caspase Ice is important for many apoptotic cell deaths and for spermatid individualization, a nonapoptotic process , 2006, Development.