Quantum algorithm for programmed cell death of Caenorhabditis elegans

During the development of Caenorhabditis elegans, through cell divisions, a total of exactly 1090 cells are generated, 131 of which undergo programmed cell death (PCD) to result in an adult organism comprising 959 cells. Of those 131, exactly 113 undergo PCD during embryogenesis, subdivided across the cell lineages in the following fashion: 98 for AB lineage; 14 for MS lineage; and 1 for C lineage. Is there a law underlying these numbers, and if there is, what could it be? Here we wish to show that the count of the cells undergoing PCD complies with the cipher laws related to the algorithms of Shor and of Grover.     

Molecular genetics of cell death in the nematode Caenorhabditis elegans

In C. elegans, cell death can be readily studied at the cellular, genetic, and molecular levels. Two types of death have been characterized in this nematode: (1) programmed cell death, which occurs as a normal component in development; and (2) pathological cell death which occurs aberrantly as a consequence of mutation. Analysis of mutations that disrupt programmed cell death in various ways has defined a genetic pathway for programmed cell death which includes genes that perform such functions as the determination of which cells die, the execution of cell death, the engulfment of cell corpses, and the digestion of DNA from dead cells. Molecular analysis is providing insightinto the nature of the molecules that function in these aspects of programmed cell death. Characterization of some genes that mutate to induce abnormal cell death has defined a novel gene family called degenerins that encode putative membrane proteins. Dominant alleles of at least two degenerin genes, mec-4 and deg-1, can cause cellular swelling and late onset neurodegeneration of specific groups of cells. © 1992 John Wiley & Sons, Inc.     

Noncanonical cell death programs in the nematode Caenorhabditis elegans

Genetic studies of the nematode Caenorhabditis elegans have uncovered four genes, egl-1 (BH3 only), ced-9 (Bcl-2 related), ced-4 (apoptosis protease activating factor-1), and ced-3 (caspase), which function in a linear pathway to promote developmental cell death in this organism. While this core pathway functions in many cells, recent studies suggest that additional regulators, acting on or in lieu of these core genes, can promote or inhibit the onset of cell death. Here, we discuss the evidence for these noncanonical mechanisms of C. elegans cell death control. We consider novel modes for regulating the core apoptosis genes, and describe a newly identified cell death pathway independent of all known C. elegans cell death genes. The existence of these noncanonical cell death programs suggests that organisms have evolved multiple ways to ensure appropriate cellular demise during development.     

Autophagy activity contributes to programmed cell death in Caenorhabditis elegans

The physiological relationship between autophagy and programmed cell death during C. elegans development is poorly understood. In C. elegans, 131 somatic cells and a large number of germline cells undergo programmed cell death. Autophagy genes function in the removal of somatic cell corpses during embryogenesis. Here we demonstrated that autophagy activity participates in germ-cell death induced by genotoxic stress. Upon γ ray treatment, fewer germline cells execute the death program in autophagy mutants. Autophagy also contributes to physiological germ-cell death and post-embryonic cell death in ventral cord neurons when ced-3 caspase activity is partially compromised. Our study reveals that autophagy activity contributes to programmed cell death during C. elegans development.     

Autophagy is required for necrotic cell death in Caenorhabditis elegans

Autophagy is the main process for bulk protein and organelle recycling in cells under extracellular or intracellular stress. Deregulation of autophagy has been associated with pathological conditions such as cancer, muscular disorders and neurodegeneration. Necrotic cell death underlies extensive neuronal loss in acute neurodegenerative episodes such as ischemic stroke. We find that excessive autophagosome formation is induced early during necrotic cell death in C. elegans. In addition, autophagy is required for necrotic cell death. Impairment of autophagy by genetic inactivation of autophagy genes or by pharmacological treatment suppresses necrosis. Autophagy synergizes with lysosomal catabolic mechanisms to facilitate cell death. Our findings demonstrate that autophagy contributes to cellular destruction during necrosis. Thus, interfering with the autophagic process may protect neurons against necrotic damage in humans.     

Molecular genetics of cell death in the nematode Caenorhabditis elegans.

In C. elegans, cell death can be readily studied at the cellular, genetic, and molecular levels. Two types of death have been characterized in this nematode: (1) programmed cell death, which occurs as a normal component in development; and (2) pathological cell death, which occurs aberrantly as a consequence of mutation. Analysis of mutations that disrupt programmed cell death in various ways has defined a genetic pathway for programmed cell death which includes genes that perform such functions as the determination of which cells die, the execution of cell death, the engulfment of cell corpses, and the digestion of DNA from dead cells. Molecular analysis is providing insight into the nature of the molecules that function in these aspects of programmed cell death. Characterization of some genes that mutate to induce abnormal cell death has defined a novel gene family called degenerins that encode putative membrane proteins. Dominant alleles of at least two degenerin genes, mec-4 and deg-1, can cause cellular swelling and late onset neurodegeneration of specific groups of cells.     

Hippo kinases maintain polarity during directional cell migration in Caenorhabditis elegans

Precise positioning of cells is crucial for metazoan development. Despite immense progress in the elucidation of the attractive cues of cell migration, the repulsive mechanisms that prevent the formation of secondary leading edges remain less investigated. Here, we demonstrate that Caenorhabditis elegans Hippo kinases promote cell migration along the anterior–posterior body axis via the inhibition of dorsal–ventral (DV) migration. Ectopic DV polarization was also demonstrated in gain‐of‐function mutant animals for C. elegans RhoG MIG‐2. We identified serine 139 of MIG‐2 as a novel conserved Hippo kinase phosphorylation site and demonstrated that purified Hippo kinases directly phosphorylate MIG‐2^S139. Live imaging analysis of genome‐edited animals indicates that MIG‐2^S139 phosphorylation impedes actin assembly in migrating cells. Intriguingly, Hippo kinases are excluded from the leading edge in wild‐type cells, while MIG‐2 loss induces uniform distribution of Hippo kinases. We provide evidence that Hippo kinases inhibit RhoG activity locally and are in turn restricted to the cell body by RhoG‐mediated polarization. Therefore, we propose that the Hippo–RhoG feedback regulation maintains cell polarity during directional cell motility.     

A morphologically conserved nonapoptotic program promotes linker cell death in Caenorhabditis elegans

Apoptosis, cell death characterized by stereotypical morphological features, requires caspase proteases. Nonapoptotic, caspase-independent cell death pathways have been postulated; however, little is known about their molecular constituents or in vivo functions. Here, we show that death of the Caenorhabditis elegans linker cell during development is independent of the ced-3 caspase and all known cell death genes. The linker cell employs a cell-autonomous death program, and a previously undescribed engulfment program is required for its clearance. Dying linker cells display nonapoptotic features, including nuclear crenellation, absence of chromatin condensation, organelle swelling, and accumulation of cytoplasmic membrane-bound structures. Similar features are seen during developmental death of neurons in the vertebrate spinal cord and ciliary ganglia. Linker cell death is controlled by the microRNA let-7 and Zn-finger protein LIN-29, components of the C. elegans developmental timing pathway. We propose that the program executing linker cell death is conserved and used during vertebrate development.     

线虫(Caenorhabditis elegans)受精卵中细胞极性的建立

早期线虫胚胎提供了一个研究发育过程的极佳模型。线虫胚胎的第一次分裂是不对称的,产生的两个子细胞在尺度的大小和发育命运上均有不同,而这些不同是由第一次有丝分裂周期中胞质决定子的不均匀分布造成的。通常相信,在受精过程中,精子所携带的中心体介导了对极性建成至关重要的胞质流动的产生。同时,细胞骨架成分被认为参与了胞质成分的定位事件。关于par基因的研究目前进展迅速,大多数par基因的突变都导致了线虫早期胚胎分裂不对称性的丧失。     

Lysosomal biogenesis and function is critical for necrotic cell death in Caenorhabditis elegans

Necrotic cell death is defined by distinctive morphological characteristics that are displayed by dying cells (Walker, N.I., B.V. Harmon, G.C. Gobe, and J.F. Kerr. 1988. Methods Achiev. Exp. Pathol. 13:18-54). The cellular events that transpire during necrosis to generate these necrotic traits are poorly understood. Recent studies in the nematode Caenorhabditis elegans show that cytoplasmic acidification develops during necrosis and is required for cell death (Syntichaki, P., C. Samara, and N. Tavernarakis. 2005. Curr. Biol. 15:1249-1254). However, the origin of cytoplasmic acidification remains elusive. We show that the alkalization of endosomal and lysosomal compartments ameliorates necrotic cell death triggered by diverse stimuli. In addition, mutations in genes that result in altered lysosomal biogenesis and function markedly affect neuronal necrosis. We used a genetically encoded fluorescent marker to follow lysosome fate during neurodegeneration in vivo. Strikingly, we found that lysosomes fuse and localize exclusively around a swollen nucleus. In the advanced stages of cell death, the nucleus condenses and migrates toward the periphery of the cell, whereas green fluorescent protein-labeled lysosomal membranes fade, indicating lysosomal rupture. Our findings demonstrate a prominent role for lysosomes in cellular destruction during necrotic cell death, which is likely conserved in metazoans.     

RNA aptamers targeting the cell death inhibitor CED-9 induce cell killing in Caenorhabditis elegans

Bcl-2 family proteins include anti- and proapoptotic factors that play important roles in regulating apoptosis in diverse species. Identification of compounds that can modulate the activities of Bcl-2 family proteins will facilitate development of drugs for treatment of apoptosis-related human diseases. We used an in vitro selection method named systematic evolution of ligands by exponential enrichment (SELEX) to isolate RNA aptamers that bind the Caenorhabditis elegans Bcl-2 homolog CED-9 with high affinity and specificity and tested whether these aptamers modulate programmed cell death in C. elegans. Five CED-9 aptamers were isolated and classified into three groups based on their predicted secondary structures. Biochemical analyses indicated that two of these aptamers, R9-2 and R9-7, and EGL-1, an endogenous CED-9-binding proapoptotic protein, bound to distinct regions of CED-9. However, these two aptamers shared overlapping CED-9 binding sites with CED-4, another CED-9-binding proapoptotic factor. Importantly ectopic expression of these two aptamers in touch receptor neurons induced efficient killing of these neurons largely in a CED-3 caspase-dependent manner. These findings suggest that RNA aptamers can be used to modulate programmed cell death in vivo and can potentially be used to develop drugs to treat human diseases caused by abnormal apoptosis.     

Many genomic regions are required for normal embryonic programmed cell death in Caenorhabditis elegans

To identify genes involved in programmed cell death (PCD) in Caenorhabditis elegans, we screened a comprehensive set of chromosomal deficiencies for alterations in the pattern of PCD throughout embryonic development. From a set of 58 deficiencies, which collectively remove approximately 74% of the genome, four distinct classes were identified. In class I (20 deficiencies), no significant deviation from wild type in the temporal pattern of cell corpses was observed, indicating that much of the genome does not contain zygotic genes that perform conspicuous roles in embryonic PCD. The class II deficiencies (16 deficiencies defining at least 11 distinct genomic regions) led to no or fewer-than-normal cell corpses. Some of these cause premature cell division arrest, probably explaining the diminution in cell corpse number; however, others have little effect on cell proliferation, indicating that the reduced cell corpse number is not a direct result of premature embryonic arrest. In class III (18 deficiencies defining at least 16 unique regions), an excess of cell corpses was observed. The developmental stage at which the extra corpses were observed varied among the class III deficiencies, suggesting the existence of genes that perform temporal-specific functions in PCD. The four deficiencies in class IV (defining at least three unique regions), showed unusually large corpses that were, in some cases, attributable to extremely premature arrest in cell division without a concomitant block in PCD. Deficiencies in this last class suggest that the cell death program does not require normal embryonic cell proliferation to be activated and suggest that while some genes required for cell division might also be required for cell death, others are not. Most of the regions identified by these deficiencies do not contain previously identified zygotic cell death genes. There are, therefore, a substantial number of as yet unidentified genes required for normal PCD in C. elegans.     

低氧预处理对新生大鼠脑低氧缺血时海马区Bcl-2和Bax表达的影响

目的：观察低氧预处理对新生大鼠脑低氧缺血时海马区Bcl-2和Bax表达的影响,探讨低氧预处理对新生大鼠脑低氧缺血损伤的保护机制。方法：7日龄新生SD大鼠随机分为正常对照组、假手术组、低氧缺血组（HIBD组）和低氧预处理组（HPC＋HIBD组）。采用免疫组织化学方法,检测各组脑组织海马区Bcl-2和Bax表达的变化。结果：与正常对照组、假手术组相比．HIBD组和HPC＋HIBD组海马区Bcl-2蛋白和Bax蛋白表达明显增多;与HIBD组相比,HPC＋HIBD组海马区Bcl-2蛋白表达明显增多,Bax蛋白表达明显减少。结论：低氧预处理后Bcl-2表达上调,Bax表达下调,可能是其保护随后脑低氧缺血损伤的机制之一。     

围产期缺氧缺血性脑损伤中星形胶质细胞的病理生理改变

转产期缺氧因性脑损的研究焦点集中在神经元上,但是,星形胶持细胞也参与缺氧缺血过程并起着关键作用。星形胶质细胞在缺氧缺血损伤中的改变是中枢神经系统中最早和最显著的,这种参与对缺氧缺血变为以及中枢神经系统是损伤还是修复这一最终发展有重要影响。目前,星形胶质细胞的作用越来越受到重视,对脑缺氧缺血过程中星形胶质细胞的病理生理变化也有了深入的研究。     

Progression from mitotic catastrophe to germ cell death in Caenorhabditis elegans lis-1 mutants requires the spindle checkpoint

Deletion of the lissencephaly disease gene LIS-1 in humans causes an extreme disorganization of the brain associated with significant reduction in cortical neurons. Here we show that deletion or RNA interference (RNAi) of Caenorhabditis elegans lis-1 results in a reduction in germline nuclei and causes a variety of cellular, developmental, and neurological defects throughout development. Our analysis of the germline defects suggests that the reduction in nuclei number stems from dysfunctional mitotic spindles resulting in cell cycle arrest and eventually programmed cell death (apoptosis). Deletion of the spindle checkpoint gene mdf-1 blocks lis-1(lf)-induced cell cycle arrest and germline apoptosis, placing the spindle checkpoint pathway upstream of the programmed cell death pathway. These results suggest that apoptosis may contribute to the cell-sparse pathology of lissencephaly.     

dad-1, an endogenous programmed cell death suppressor in Caenorhabditis elegans and vertebrates.

Programmed cell death (apoptosis) is a normally occurring process used to eliminate unnecessary or potentially harmful cells in multicellular organisms. Recent studies demonstrate that the molecular control of this process is conserved phylogenetically in animals. The dad-1 gene, which encodes a novel 113 amino acid protein, was originally identified in a mutant hamster cell line (tsBN7) that undergoes apoptosis at restrictive temperature. We have identified a dad-1 homologue in Caenorhabditis elegans (Ce-dad-1) whose predicted product is > 60% identical to vertebrate DAD-1. A search of the sequence databases indicated that DAD-1-like proteins are also expressed in two plant species. Expression of either human dad-1 or Ce-dad-1 under control of a C.elegans heat-shock-inducible promoter resulted in a reduction in the number of programmed cell death corpses visible in C.elegans embryos. Extra surviving cells were present in these animals, indicating that both the human and C.elegans dad-1 genes can suppress developmentally programmed cell death. Ce-dad-1 was found to rescue mutant tsBN7 hamster cells from apoptotic death as efficiently as the vertebrate genes. These results suggest that dad-1, which is necessary for cell survival in a mammalian cell line, is sufficient to suppress some programmed cell death in C.elegans.     

Cell plasticity in Caenorhabditis elegans: from induced to natural cell reprogramming

Achieving controlled reprogramming of differentiated cells into a desired cell type would open new opportunities in stem-cell biology and regenerative medicine. Experimentation on cell reprogramming requires a model in which cell conversion can be induced and tracked individually. The tiny nematode, Caenorhabditis elegans, owing to its known cellular lineage, allows the study of direct cell type conversion with a single-cell resolution. Indeed, recent advances have shown that despite its invariant cell lineage, cellular identities can be reprogrammed, leading to cell conversion in vivo. In addition, natural transdifferentiation events occur in the worm, providing a powerful model for the study of cellular plasticity in a physiological cellular microenvironment. Here, we review pioneer studies on induced and naturally occurring reprogramming events in C. elegans and the new notions that have emerged.     

Alterations in cell lineage following laser ablation of cells in the somatic gonad of Caenorhabditis elegans

The postembryonic cell lineage of the somatic gonad is essentially invariant in Caenorhabditis elegans (J.E. Kimble and D. Hirsh, 1979, Develop. Biol.70, 396–417). The two exceptions to this rule of invariance involve a natural ambiguity in the ancestry of certain cells such that each of two precursor cells assumes one of two alternative fates in a given animal. In this paper, experiments are reported in which laser microsurgery is used to kill individual cells in the developing somatic gonad. Such intervention perturbs the normal environment of the remaining cells; a change observed in the expected behavior of these cells suggests that extrinsic cues may normally play a role in controlling that behavior. Several different lineage alterations have been observed after laser microsurgery in the somatic gonad. These include switches in the type of lineage followed by a given precursor cell, reversals in lineage polarity, duplications of a lineage, and alteratiions in the number of cells produced in the lineage. The only cases in which cells switch from one lineage type to another involve pairs of cells which exhibit natural ambiguity. In most cases, the interactions inferred from these changes seem to occur between neighboring somatic gonadal cells. In one case, induction of the vulva, the interaction occurs between a single somatic gonadal cell, the anchor cell, and the precursors to the vulva in a neighboring tissue, the hypodermis. The roles of intrinsic and extrinsic cues in controlling normally invariant cell lineages are discussed.     

Single‐cell dynamics of chromatin activity during cell lineage differentiation in Caenorhabditis elegans embryos

Elucidating the chromatin dynamics that orchestrate embryogenesis is a fundamental question in developmental biology. Here, we exploit position effects on expression as an indicator of chromatin activity and infer the chromatin activity landscape in every lineaged cell during Caenorhabditis elegans early embryogenesis. Systems‐level analyses reveal that chromatin activity distinguishes cellular states and correlates with fate patterning in the early embryos. As cell lineage unfolds, chromatin activity diversifies in a lineage‐dependent manner, with switch‐like changes accompanying anterior–posterior fate asymmetry and characteristic landscapes being established in different cell lineages. Upon tissue differentiation, cellular chromatin from distinct lineages converges according to tissue types but retains stable memories of lineage history, contributing to intra‐tissue cell heterogeneity. However, the chromatin landscapes of cells organized in a left–right symmetric pattern are predetermined to be analogous in early progenitors so as to pre‐set equivalent states. Finally, genome‐wide analysis identifies many regions exhibiting concordant chromatin activity changes that mediate the co‐regulation of functionally related genes during differentiation. Collectively, our study reveals the developmental and genomic dynamics of chromatin activity at the single‐cell level.