Wang, Guoqiang et al. (2015) International Worm Meeting "Probing the Mechanisms by Which Exercise Enhances Axon Regrowth."

Driscoll, Monica, Wang, Guoqiang, Song, Isaac, Reina, Christopher

[International Worm Meeting, 2015]

In mammalian neuronal injury models, exercise improves neuronal regeneration, although the cellular and molecular mechanisms operative remain largely unclear. We found that pre-axotomy swim training of young age Caenorhabditis elegans can enhance axon regrowth consequent to single neurite severing. Even more striking is that a short period of post-axotomy exercise can also significantly enhance regrowth. C. elegans is thus a novel model with which to define the genetic pathways that link exercise to neuronal regeneration capacity.We have initiated our studies with a focus on the classical signaling pathways that confer mammalian exercise adaptation, such as those involving Ca2+, AMPK, PGC-1alpha and p38 kinase. A common outcome of different activating pathways is enhanced mitochondrial biogenesis. We have found that increased mitochondrial biogenesis via limiting the activity of the gei-8/NCoR gene, which encodes a negative regulator of mitochondrial biogenesis, can significantly enhance axon regrowth. On the other hand, genetically uncoordinated animals exhibit basically wild type levels of axon regrowth after laser axotomy-so baseline crawling activity does not seem to induce any particular regeneration signal. Taken together, our results indicate exercise might potentiate regrowth by activating physiological stress responses to intensive exercise. We have found that aak-2/AMPK is normally required for exercise strength adaptation. Interestingly, an aak-2/AMPK mutation does not suppress the increased regrowth of severed ALM neurons in the post-axotomy exercise paradigm. This observation indicates that the AMPK signaling pathway is not essential for potentiating axon regrowth by post-injury exercise. An alternative hypothesis is that exercise enhances axon regrowth by increasing stimulation to the injured neuron. For example, the mec-4 mec-10 double mutant, defective for gentle and harsh touch responses, is strongly inhibited for axon regrowth of ALM neurons, although the effect of exercise on the mec-4 mec-10 mutant is waiting to be tested. In general, we will report on findings relevant to the cellular and molecular mechanisms of exercise-enhanced neuronal regeneration of individual axotomized neurons.

Wang, Guoqiang et al. (2021) International Worm Meeting "Isocitrate lyase protects Caenorhabditis elegans from mitochondrial superoxide stress through activation of the mitochondrial unfolded protein response"

LeValley, Stephanie, Laranjeiro, Ricardo, Driscoll, Monica, Van Raamsdonk, Jeremy, Wang, Guoqiang

[International Worm Meeting, 2021]

Mitochondrial energy metabolism produces ATP to support cellular activities at the same time that superoxide, the byproduct of electron transport, can either trigger signaling responses or post threats to cellular functions. Conserved superoxide dismutase (SOD) functions in protection by scavenging superoxide and converting to H2O2. Eliminating mitochondrial SODs causes neonatal/embryonic lethality in both mice and flies, but not in the nematode C. elegans. C. elegans have 2 mitochondrial sod genes (sod-2 and sod-3) while mice and flies have one. Eliminating mitochondrial sod-2 can actually increase C. elegans lifespan. The mechanism causing C. elegans to be resistant to mitochondrial superoxide stress is still unknown. A metabolic pathway, named glyoxylate shunt, distinguishes C. elegans from mice and flies. As an alternative branch to the tricarboxylic acid (TCA) cycle, the glyoxylate shunt is missing in both mice and flies. The icl-1 isocitrate lyase gene encodes the key enzymes of the glyoxylate shunt in C. elegans. We found that icl-1 is critical for protection against embryonic lethality when mitochondrial SODs are absent. The mitochondrial sod-2;sod-3 double mutant exhibits embryonic lethality in the range of 5% to 9%, which is associated with elevated icl-1 gene expression. We crossed the sod-2;sod-3 mutant to an icl-1 null allele, icl-1(ok531), and found that the embryonic lethality rose to ~ 60%. Thus, icl-1 protects against embryonic lethality in the absence of mitochondrial SOD. To explore the mechanism by which icl-1 protects against embryonic lethality, we examined its role in activating the mitochondrial unfolded protein response (UPRmt). We found that icl-1 is required for the efficient activation of the UPRmt and the UPRmt is required to suppress embryonic/neonatal lethality. We also found that the UPRmt plays a significant role in protecting against mitochondrial superoxide stress, as the constitutive activation of UPRmt via atfs-1(gf)can bypass the icl-1 requirement. Our study reveals a pathway that involves the C. elegans specific glyoxylate shunt and a much-conserved UPRmt to counteract mitochondrial superoxide stress. This pathway might be manipulated in developing synthetic biological tools or innovative pharmacological methods to treat diseases that are related to mitochondrial superoxide stress.

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.

Hall DH et al. (1994) Worm Breeder's Gazette "Cytology of Degenerin-Induced Cell Death in the PVM Neuron"

Driscoll MA, Chalfie M, Gu GQ, Hall DH, Gong L

[Worm Breeder's Gazette, 1994]

Cytology of degenerin-induced cell death in the PVM neuron David H. Hall, Guoqiang Gu+, Lei Gong#, Monica Driscoll#, and Martin Chalfie+, * Dept. Neuroscience, Albert Einstein College of Medicine, Bronx, N.Y. 10461 + Dept. Biological Sciences, Columbia University, New York, N.Y. 10027 # Dept. Molecular Biology and Biochemistry, Rutgers University, Piscataway, N.J. 08855

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.

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.