Programmed elimination of cells by caspase-independent cell extrusion in C. elegans

Denning, Daniel P.; Hatch, Victoria; Horvitz, H. Robert

doi:10.1038/nature11240

Cited by 62 publications

(113 citation statements)

References 38 publications

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“…A recent report showed that PIG-1, PAR-4, STRD-1, and two of the MOP25 homologs affect several caspase-independent cell deaths (Denning et al 2012) (see Discussion), further supporting our hypothesis that these genes act together in the same pathway.…”

Section: Par-4 and Strd-1 Function In The Same Pathway As Pig-1 And Psupporting

confidence: 76%

“…For example, we showed that pig-1 and strd-1 regulate the PLM lineage ( Figure 3B), suggesting that these genetic interactions are not specific for the Q.p lineage. Moreover, Denning et al (2012) recently reported that pig-1, par-4, and strd-1 act together to regulate the death of a subset of cells that die early in the C. elegans embryo. These cells die by a caspase-independent mechanism and are shed from the embryo in caspase-deficient mutants.…”

Section: Discussionmentioning

confidence: 99%

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Caenorhabditis elegans PIG-1/MELK Acts in a Conserved PAR-4/LKB1 Polarity Pathway to Promote Asymmetric Neuroblast Divisions

et al. 2013

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Asymmetric cell divisions produce daughter cells with distinct sizes and fates, a process important for generating cell diversity during development. Many Caenorhabditis elegans neuroblasts, including the posterior daughter of the Q cell (Q.p), divide to produce a larger neuron or neuronal precursor and a smaller cell that dies. These size and fate asymmetries require the gene pig-1, which encodes a protein orthologous to vertebrate MELK and belongs to the AMPK-related family of kinases. Members of this family can be phosphorylated and activated by the tumor suppressor kinase LKB1, a conserved polarity regulator of epithelial cells and neurons. In this study, we present evidence that the C. elegans orthologs of LKB1 (PAR-4) and its partners STRAD (STRD-1) and MO25 (MOP-25.2) regulate the asymmetry of the Q.p neuroblast division. We show that PAR-4 and STRD-1 act in the Q lineage and function genetically in the same pathway as PIG-1. A conserved threonine residue (T169) in the PIG-1 activation loop is essential for PIG-1 activity, consistent with the model that PAR-4 (or another PAR-4-regulated kinase) phosphorylates and activates PIG-1. We also demonstrate that PIG-1 localizes to centrosomes during cell divisions of the Q lineage, but this localization does not depend on T169 or PAR-4. We propose that a PAR-4-STRD-1 complex stimulates PIG-1 kinase activity to promote asymmetric neuroblast divisions and the generation of daughter cells with distinct fates. Changes in cell fate may underlie many of the abnormal behaviors exhibited by cells after loss of PAR-4 or LKB1.A SYMMETRIC cell divisions produce daughter cells with distinct fates, a process important for generating cell diversity in organisms as different as bacteria, plants, and animals. In Caenorhabditis elegans, asymmetric divisions of neuroblasts often produce cells fated to die. The posterior daughter of the Q cell (Q.p) neuroblasts, for example, divide to produce a neuronal precursor and a cell that dies, but how this fate asymmetry is generated in these divisions is poorly understood. PIG-1 regulates asymmetric neuroblast divisions that generate apoptotic cells by controlling spindle positioning, myosin distribution, and daughter cell fate (Cordes et al. 2006;Ou et al. 2010). PIG-1 is the sole C. elegans ortholog of MELK (maternal embryonic leucine zipper kinase), a serine/ threonine kinase that has been implicated in many developmental processes including stem cell renewal, apoptosis, cell cycle progression, and spliceosome assembly (Davezac et al. 2002;Vulsteke et al. 2004;Nakano et al. 2005;Lin et al. 2007;Jung et al. 2008). MELK and PIG-1 represent a subgroup of a large family of serine/threonine kinases that include molecules like PAR-1 and SAD-1, which regulate cell polarity, and AMPKs, which regulate metabolic processes (Bright et al. 2009). These family members are often regulated directly by the LKB1 kinase (Lizcano et al. 2004).Loss of the tumor suppressor LKB1 causes Peutz-Jeghers syndrome, a disease in humans that is characterized...

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Section: Par-4 and Strd-1 Function In The Same Pathway As Pig-1 And Psupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Caenorhabditis elegans PIG-1/MELK Acts in a Conserved PAR-4/LKB1 Polarity Pathway to Promote Asymmetric Neuroblast Divisions

et al. 2013

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“…Denning et al [8] went further to find the regulators of the death, which is conferred by shedding. Again the information provided by the invariant developmental lineage, and the ability to study development at the cellular level came to their aide.…”

mentioning

confidence: 99%

“…A recent Nature paper by Denning et al [8] describes a novel form of developmentally regulated programed cell death in C. elegans. This cell death, which the authors refer to as cell shedding, is independent of the CED-3 caspase as well as of the three further caspases encoded in the C. elegans genome.…”

mentioning

confidence: 99%

If you don't want them shed them

Pourkarimi

Gartner

2012

Cell Res

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“…C. elegans harbors only one ortholog of Xk proteins, CED-8, known to participate in the phagocytic removal of apoptotic corpses [6]. To determine the role of CED-8 in PS exposure, the authors took advantage of the "floater" assay, which is based on the appearance of floating cells ("floaters") that have detached from developing C. elegans embryos defective for apoptotic cell phagocytosis [7]. Nagata's group discovered that ced-8 deficiency leads to the accumulation of floaters.…”

mentioning

confidence: 99%