Genetic control of programmed cell death in the Caenorhabditis elegans hermaphrodite germline.

Development of the nematode Caenorhabditis elegans is highly reproducible and the fate of every somatic cell has been reported. We describe here a previously uncharacterized cell fate in C. elegans: we show that germ cells, which in hermaphrodites can differentiate into sperm and oocytes, also undergo apoptotic cell death. In adult hermaphrodites, over 300 germ cells die, using the same apoptotic execution machinery (ced-3, ced-4 and ced-9) as the previously described 131 somatic cell deaths. However, this machinery is activated by a distinct pathway, as loss of egl-1 function, which inhibits somatic cell death, does not affect germ cell apoptosis. Germ cell death requires ras/MAPK pathway activation and is used to maintain germline homeostasis. We suggest that apoptosis eliminates excess germ cells that acted as nurse cells to provide cytoplasmic components to maturing oocytes.

[1]  John Calvin Reed,et al.  Bcl-2 Targets the Protein Kinase Raf-1 to Mitochondria , 1996, Cell.

[2]  M. Hengartner.  Apoptosis CED-4 is a stranger no more , 1997, Nature.

[3]  Hilla Peretz,et al.  Ju n 20 03 Schrödinger ’ s Cat : The rules of engagement , 2003 .

[4]  F. Maytag.  Evolution , 1996, Arch. Mus. Informatics.

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

[6]  H. Horvitz,et al.  Mechanisms and functions of cell death. , 1991, Annual review of cell biology.

[7]  S. Brenner.  The genetics of Caenorhabditis elegans. , 1974, Genetics.

[8]  D. Riddle.  C. Elegans II , 1998 .

[9]  H. Horvitz,et al.  Two C. elegans genes control the programmed deaths of specific cells in the pharynx. , 1991, Development.

[10]  H. Horvitz,et al.  The ins and outs of programmed cell death during C. elegans development. , 1994, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[11]  S. Ward,et al.  7 Germ-line Development and Fertilization , 1988 .

[12]  B. Fowlkes,et al.  Selective events in T cell development. , 1994, Annual review of immunology.

[13]  John Calvin Reed.  Bcl-2 and the regulation of programmed cell death , 1994, The Journal of cell biology.

[14]  K. Guan,et al.  Three genes of the MAP kinase cascade, mek-2, mpk-1/sur-1 and let-60 ras, are required for meiotic cell cycle progression in Caenorhabditis elegans. , 1995, Development.

[15]  S. Brenner,et al.  Mutations causing transformation of sexual phenotype in the nematode Caenorhabditis elegans. , 1977, Genetics.

[16]  P. Sternberg,et al.  Ras pathways in Caenorhabditis elegans. , 1995, Current opinion in genetics & development.

[17]  L. Wang,et al.  [Genetic control of programmed cell death]. , 1996, Sheng li ke xue jin zhan [Progress in physiology].

[18]  S. Korsmeyer,et al.  Bad, a heterodimeric partner for Bcl-xL and Bcl-2, displaces bax and promotes cell death , 1995, Cell.

[19]  M. Hengartner.  Apoptosis: Death cycle and Swiss army knives , 1998, Nature.

[20]  H. Horvitz,et al.  Genetic control of programmed cell death in the nematode C. elegans , 1986, Cell.

[21]  H. Horvitz,et al.  The C. elegans Protein EGL-1 Is Required for Programmed Cell Death and Interacts with the Bcl-2–like Protein CED-9 , 1998, Cell.

[22]  B. Meyer.  Sex Determination and X Chromosome Dosage Compensation , 1997 .

[23]  J. Sulston,et al.  Mutations affecting programmed cell deaths in the nematode Caenorhabditis elegans. , 1983, Science.

[24]  H. Lipkin.  Where is the ?c? , 1978 .

[25]  H. Horvitz,et al.  The genetics of programmed cell death in the nematode Caenorhabditis elegans. , 1994, Cold Spring Harbor symposia on quantitative biology.

[26]  M. Hengartner,et al.  Caenorhabditis elegans gene ced-9 protects cells from programmed cell death , 1992, Nature.

[27]  J. Hodgkin.  More sex-determination mutants of Caenorhabditis elegans. , 1980, Genetics.

[28]  R. Ellis,et al.  Control of germ cell differentiation in Caenorhabditis elegans. , 1994, Ciba Foundation symposium.

[29]  S. Cory,et al.  The Bcl-2 protein family: arbiters of cell survival. , 1998, Science.

[30]  J. Tilly.  Apoptosis and ovarian function. , 1996, Reviews of reproduction.

[31]  L. Peso,et al.  Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. , 1997, Science.

[32]  T. Schedl,et al.  gld-1, a tumor suppressor gene required for oocyte development in Caenorhabditis elegans. , 1995, Genetics.

[33]  T. Schedl.  Developmental Genetics of the Germ Line , 1997 .

[34]  D. Chao,et al.  BCL-2 family: regulators of cell death. , 1998, Annual review of immunology.

[35]  J. Starck,et al.  Role of the gonad cytoplasmic core during oogenesis of the nematode Caenorhabditis elegans , 1984, Biology of the cell.

[36]  Thomas de Quincey.  [C] , 2000, The Works of Thomas De Quincey, Vol. 1: Writings, 1799–1820.

[37]  T. Schedl,et al.  Somatic control of germ cell development in Caenorhabditis elegans , 1994 .

[38]  S. Korsmeyer.  BCL-2 gene family and the regulation of programmed cell death. , 1995, Cancer research.

[39]  J. Sulston,et al.  Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. , 1977, Developmental biology.

[40]  J Cairns,et al.  Cold spring harbor. , 1991, Science.

[41]  M. Driscoll,et al.  Molecular genetics of cell death in the nematode Caenorhabditis elegans. , 1992, Journal of neurobiology.

[42]  J. Sulston,et al.  The DNA of Caenorhabditis elegans. , 1974, Genetics.

[43]  A D Chisholm,et al.  Cell Lineage , 1898, The American Naturalist.

[44]  Horvitz,et al.  Genes required for the engulfment of cell corpses during programmed cell death in Caenorhabditis elegans. , 1991, Genetics.

[45]  J. Sulston,et al.  The embryonic cell lineage of the nematode Caenorhabditis elegans. , 1983, Developmental biology.

[46]  H. Horvitz,et al.  Gonadal cell lineages of the nematode Panagrellus redivivus and implications for evolution by the modification of cell lineage. , 1981, Developmental biology.

[47]  R. Weichselbaum,et al.  Overexpression of Bcl-XL by cytotoxic drug exposure confers resistance to ionizing radiation-induced internucleosomal DNA fragmentation. , 1995, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[48]  S. Fesik,et al.  Identification of a novel regulatory domain in Bcl‐xL and Bcl‐2 , 1997, The EMBO journal.

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

[50]  D. Hirsh,et al.  The postembryonic cell lineages of the hermaphrodite and male gonads in Caenorhabditis elegans. , 1979, Developmental biology.

[51]  Xiaodong Wang,et al.  Apaf-1, a Human Protein Homologous to C. elegans CED-4, Participates in Cytochrome c–Dependent Activation of Caspase-3 , 1997, Cell.

[52]  Shai Shaham,et al.  The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1β-converting enzyme , 1993, Cell.

[53]  H. Horvitz,et al.  The Caenorhabditis elegans cell death gene ced-4 encodes a novel protein and is expressed during the period of extensive programmed cell death. , 1992, Development.

[54]  H. Horvitz,et al.  C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2 , 1994, Cell.

[55]  H. Horvitz,et al.  The Caenorhabditis elegans cell-death protein CED-3 is a cysteine protease with substrate specificities similar to those of the human CPP32 protease. , 1996, Genes & development.

[56]  H. Steller,et al.  Programmed cell death during Drosophila embryogenesis. , 1993, Development.

[57]  J. Sulston,et al.  The Caenorhabditis elegans male: postembryonic development of nongonadal structures. , 1980, Developmental biology.

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