Infarinato N (2019) J Cell Biol "Xiaochen Wang: Building up our understanding of breaking down."

Infarinato N

[J Cell Biol, 2019]

Wang studies lysosomal degradation pathways using <i>C. elegans</i> as a model system.

Wang JT et al. (2014) Curr Biol "P granules."

Seydoux G, Wang JT

[Curr Biol, 2014]

Wang and Seydoux discuss the functional importance of P granules - the germline-specific RNA granules of C. elegans.

Munro E (2017) Dev Cell "Protein Clustering Shapes Polarity Protein Gradients."

Munro E

[Dev Cell, 2017]

In this issue of Developmental Cell, Dickinson etal. (2017) and Rodriguez etal. (2017), along with Wang etal. (2017) in Nature Cell Biology, show how PAR protein oligomerization can dynamically couple protein diffusion and transport by cortical flow to control kinase activity gradients and polarity in the C.elegans zygote.

Rashid S et al. (2017) Dev Cell "Packing on the Pounds in Response to Bacterial Growth Conditions."

Rashid S, MacNeil LT

[Dev Cell, 2017]

Reporting in Nature Cell Biology, Lin and Wang (2017) show that bacterial methyl metabolism impacts host mitochondrial dynamics and lipid storage in C.elegans. The authors propose a model whereby bacterial metabolic products regulate a nuclear hormone receptor that promotes lipid accumulation through expression of a secreted Hedgehog-like protein.

Vincenz L et al. (2014) Cell "Sugarcoating ER Stress."

Vincenz L, Hartl FU

[Cell, 2014]

The hexosamine biosynthetic pathway (HBP) generates metabolites for protein N- and O-glycosylation. Wang et al. and Denzel et al. report a hitherto unknown link between the HBP and stress in the endoplasmic reticulum. These studies establish the HBP as a critical component of the cellular machinery of protein homeostasis.

Sural S (2023) Trends Genet "Protecting axons in grandchildren."

Sural S

[Trends Genet, 2023]

Prenatal exposure to environmental agents can influence the fitness of not only the fetus, but also subsequent generations. In a recent study, Wang et al. demonstrated that feeding ursolic acid (UA), a plant-derived compound, to Caenorhabditis elegans mothers during their reproductive period prevented neurodegeneration in not only their offspring, but also the F2 progeny.

Beate Gerstbrein et al. (2002) East Coast Worm Meeting "One Goal - three Approaches: Exploring Genetics of Necrotic-like Cell Death in C. elegans"

Beate Gerstbrein, Chasmar Schreiber, Guannan Wang, Vienna Lo, Keli Xu, Monica Driscoll

[East Coast Worm Meeting, 2002]

Necrotic cell death is a main contributor to neurodegenerative conditions in humans, yet the mechanisms underlying necrosis are poorly understood. In C. elegans, a number of genetic defects can cause necrotic-like cell degeneration, including dominant alleles specifying hyperactive variants of the MEC-4 and DEG-1 degenerin ion-channel subunits, a dominant allele of the deg-3 gene encoding a non-desensitizing acetylcholine receptor subunit, and a transgenically-expressed constitutively-activated mutant of the G-protein subunit GalphaS . The morphological changes induced by these cytotoxic insults include cell swelling and vacuolization, and are microscopically distinct from apoptotic cell death. In addition, key executors of apoptosis are not required for the initiation or progression of necrotic cell death. Interestingly, the membranous inclusions occurring at the early stage of necrosis resemble ultrastructural features seen during some excitotoxic cell death in mammalian models and aberrant aggregates are common features in several human neurodegenerative disorders. We are focusing on a gain-of-function mutation in the touch mediating degenerin ion-channel subunit mec-4(d) to study molecular requirements for necrotic-like cell death. When mutated, the MEC-4(D) ion channel is locked open, leading to increased cation influx, which triggers the degeneration of the touch cells. In a screen for suppressors of ectopic mec-4(d) expression, we isolated 13 suppressor alleles in previously unknown loci influencing cell. One of the loci was identified as the Ca2+ -binding protein calreticulin [Xu K. et al., 2001], suggesting elevated intracellular Ca2+ plays a critical (and conserved) role in necrosis. Here we report on the progress of the mapping and characterization of the remaining suppressor alleles. Our long term goal is to clone these loci to learn about molecular details of necrotic death mechanisms. In a systematic attempt to identify additional key executors of necrotic cell death, we are using a commercially available RNAi feeding library, which targets the expression of 2,800 transcripts on chromosome I. We feed mec-4(d) worms with each individual RNAi clone and subsequently score for suppression of touch neuron degeneration. Halfway through this screen, we identified 10 clones with significant suppressor effects. Several of the genes we identified are involved in Ca2+ -regulation. This includes calpains. In ischemic brain injury (e.g., in stroke) in mammals, abnormally high concentrations of intracellular Ca2+ trigger a cascade of proteolytic events, that lead eventually to the dismantling of the affected cells. Calpains are a group of Ca2+ regulated cysteine proteases, that participate in mammalian necrosis. The completed sequence of the worm genome predicts 16 calpain-like genes with homology to mammalian calpains. We are in the course of examining the involvement of each of these genes in the progression of necrotic-like cell death induced by mec-4(d) using RNAi. Our goal is to order calpains into a "pathway" with other genes that influence the death process.

Spalthoff C et al. (2016) Neuron "Sensing pH with TMCs."

Gopfert MC, Spalthoff C

[Neuron, 2016]

Transmembrane channel-like (TMC) proteins have been implicated in hair cell mechanotransduction, Drosophila proprioception, and sodium sensing in the nematode C.elegans. In this issue of Neuron, Wang etal. (2016) report that C.elegans TMC-1 mediates nociceptor responses to high pH, not sodium, allowing the nematode to avoid strongly alkaline environments in which most animals cannot survive.

Beate Gerstbrein et al. (2003) International Worm Meeting "Molecular, Genetic and Pharmacological Analysis of Necrotic Cell Death Mechanisms in C. elegans"

Beate Gerstbrein, Vienna Lo, Monica Driscoll, Wenying Zhang, Guannan Wang, Chasmar Schreiber

[International Worm Meeting, 2003]

Necrotic cell death is a major contributor to the devastating neuronal damage that accompanies ischemia, stroke, injury and neurodegenerative disease. This mode of cell death is distinct from apoptosis, but importantly, also appears to feature mechanistic aspects conserved from nematodes to mammals. If so, dissection of necrosis mechanisms in C. elegans will provide novel insights that will extend understanding of human disease and injury. Several distinct genetic conditions in C. elegans can elicit neuronal death that morphologically resembles mammalian neurons undergoing excitotoxic death consequent to channel hyperactivation. One of the best studied of these death-inducing situations affects MEC-4, a member of the degenerin family of Na+-ion channels. A neomorphic allele, mec-4(d), specifies an AA substitution close to the channel pore that is thought to initiate cell death by impeding proper control of the ion channel gating mechanism. This leads to increased ion influx, multilamellar inclusions, cell swelling, degradation of cellular contents and eventual death. We have previously shown that null alleles of calreticulin, a chaperone and Ca2+-store modulator, are potent suppressors of mec-4(d)-induced death. Furthermore, reduction-of-function alleles of ER Ca2+-release channels IP3R (itr-1) and the ryanodine receptor (unc-68), significantly suppress cell death. Our data suggests that ER Ca2+ release plays a critical role in the progression through necrosis. We are working to elaborate the mechanism by which an initial influx of Na+ results in a catastrophic release of Ca2+ from the ER. We will present data from genetic as well as pharmacological experiments that are designed to investigate the Ca2+ requirements in dying neurons. A great power of the C. elegans model is the ability to conduct unbiased screens that identify novel genes that affect conserved processes. To better define molecular necrosis mechanisms, we are conducting a genome-wide survey to identify genes needed for efficient progression through necrosis. We will report on our progress.

Matsumoto M et al. (2005) Cell Metab "All roads lead to FoxO."

Accili D, Matsumoto M

[Cell Metab, 2005]

Stress-activated kinases control metabolism by antagonizing the early steps of insulin signal transduction. Two papers now demonstrate that Jnk, the prototypical stress-activated kinase, controls life span in Drosophila and C. elegans by promoting phosphorylation of the forkhead protein FoxO (Oh et al., 2005; Wang et al., 2005). The findings provide yet another mechanism by which metabolic and stress responses are integrated via phosphorylation of FoxO proteins.