Establishing the Drosophila Larval Neuroblast as a System to Study Regulated Cell Death in vivo.

[摘要] Programmed cell death is often thought of as a developmental process that is genetically hardwired to occur in the organism in a spatially and temporally specific manner.However, many forms of regulated cell death occur in response to pathological injury or environmental stress.Cell death in response to injury, in particular genotoxic stress, is well documented, but the pathways by which damage is translated to cell death have remained largely elusive.Furthermore, many cell death pathways function independently of the well-known process of apoptosis.These alternative regulated cell death pathways are likely controlled by novel molecular mechanisms.While examining mutations that cause loss of neural stem cells (neuroblasts) in Drosophila larval brains, we discovered a novel mechanism elicited by Cdc20/Fizzy (Fzy) that maintains neuroblasts by promoting their survival.We identified two fzy loss-of-function mutations that specifically led to neuroblast loss without perturbing the proliferation of other cell types.Consistently, mutant Fzy or Cdc20 carrying the analogous mutation can substitute for wild-type Cdc20 and restore cell cycle progression in fzy mutant brains.Furthermore, these fzy mutant neuroblasts do not display characteristics indicative of known cell death pathways, such as apoptosis, autophagic cell death, or mitotic catastrophe.Instead, morphological and functional analyses strongly suggest that Fzy maintains neuroblasts by suppressing necrotic cell death.Inactivating the function of apoptosis inducing factor (aif) or c-Jun N-terminal kinase (JNK) signaling prolonged the survival of fzy mutant neuroblasts, while ectopically activating JNK signaling triggers premature necrotic cell death in neuroblasts.These results suggest that JNK signaling and aif play a role in neuroblast necrosis. Loss of telomere capping proteins or chaperonin proteins required for spindle formation caused a similar necrosis phenotype as the fzy mutant neuroblasts.These mutations also caused DNA damage or cell cycle disruption.Furthermore, over-expression of the cell cycle checkpoint protein p53 also caused neuroblast necrosis.Importantly, Fzy expression was decreased in each of these mutations.We propose a novel necrotic cell death mechanism triggered by catastrophic damage of neuroblasts which leads to up-regulation of p53.Increased p53 activity results in loss of Fzy expression and Fzy-dependent necrotic cell death.

[发布机构] University of Michigan

[效力级别] necrotic cell death

[关键词] stem cell survival;necrotic cell death;cell survival checkpoint;genotoxic stress;Molecular;Cellular and Developmental Biology;Science;Cellular and Molecular Biology