Cell-nonautonomous regulation of C. elegans germ cell death by kri-1.
Programmed cell death (or apoptosis) is an evolutionarily conserved, genetically controlled suicide mechanism for cells that, when deregulated, can lead to developmental defects, cancers, and degenerative diseases. In C. elegans, DNA damage induces germ cell death by signaling through cep-1/p53, ultimately leading to the activation of CED-3/caspase. It has been hypothesized that the major regulatory events controlling cell death occur by cell-autonomous mechanisms, that is, within the dying cell. In support of this, genetic studies in C. elegans have shown that the core apoptosis pathway genes ced-4/APAF-1 and ced-3/caspase are required in cells fated to die. However, it is not known whether the upstream signals that activate apoptosis function in a cell-autonomous manner. Here we show that kri-1, an ortholog of KRIT1/CCM1, which is mutated in the human neurovascular disease cerebral cavernous malformation, is required to activate DNA damage-dependent cell death independently of cep-1/p53. Interestingly, we find that kri-1 regulates cell death in a cell-nonautonomous manner, revealing a novel regulatory role for nondying cells in eliciting cell death in response to DNA damage.
Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Shu
S
Ito
Sebastian
S
Greiss
Anton
A
Gartner
W Brent
WB
Derry
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology*; D005854:Germ Cells / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008954:Models, Biological; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D029742:Caenorhabditis elegans Proteins; D047908:Intracellular Signaling Peptides and Proteins; C517777:KRI-1 protein, C elegans