Wang, Meng et al. (2009) International Worm Meeting "Genetic analysis of the relationship between reproduction and longevity."

Ruvkun, Gary, Wang, Meng

[International Worm Meeting, 2009]

Reproduction and aging are intertwined phenomena throughout metazoan phylogeny. During aging, reproductive abilities decline and many organisms including C. elegans display a sharp decrease in progeny production, which refers to reproductive senescence. In human, the transition to reproductive senescence is associated with age-related diseases. Genetic studies have suggested that signals from the reproductive system influence organism lifespan in worms and fruit flies. In our studies, we have investigated the mechanistic interrelationship between reproduction and longevity. To investigate the molecular mechanisms underlying reproductive senescence, we have conducted a genome-wide RNA interference (RNAi) screen searching for genes whose inactivation postpones reproductive senescence. From the screen, we identified 94 genes when inactivated result in delayed reproductive senescence. Animals with reduced insulin/IGF-1 or serotonin signaling have delayed reproductive senescence, which is suppressed by inactivation of the Forkhead transcription factor. We have analyzed the genetic interactions of the newly identified genes with insulin receptor/daf-2, serotonin biosynthesis enzyme/tph-1 and Forkhead transcription factor/daf-16. These analyses have identified new factors in insulin and serotonin signaling, and also novel regulators of reproductive senescence. Further characterization has revealed the roles of these genes in regulation of stress resistance, fat metabolism and organism lifespan. These studies provide insights to the interaction between reproductive senescence and somatic aging and the mechanisms by which reproductive senescence is regulated. This work is supported by Life Sciences Research Foundation and Ellison Medical Foundation Fellowships.

Wang, Meng et al. (2009) International Worm Meeting "Fat metabolism: a missing link between reproduction and longevity."

Wang, Meng, Ruvkun, Gary, O'Rourke, Eyleen

[International Worm Meeting, 2009]

A precise balance of fat mobilization and storage is a basic feature of animal physiology. The endocrine role of adipose tissue in regulation of animal lifespan has been implied by genetic studies in both invertebrate and vertebrate organisms. However it is unclear how fat metabolism is related to lifespan control. As an energy-intensive process, reproduction has a significant impact on fat metabolism. In C. elegans and Drosophila, signals from the reproductive system regulate organism lifespan. Thus, understanding the mechanisms by which fat metabolism is coupled to reproductive cues may shed light on the systemic regulation of fat metabolism and provide insights on the control of aging. In our studies, we have identified a specific fat lipase (lipl-4) that connects lipid hydrolysis, germline stem cell proliferation and longevity in C. elegans. We found that germline stem cell arrest promotes systemic lipolysis by inducing the expression of the lipase. This lipase is also necessary upon germline stem cell arrest to prolong lifespan. Strikingly, constitutive expression of the lipase in fat storage tissue induces lipid hydrolysis and leads to longevity. The lifespan extension is independent of the Forkhead transcription factor/Daf-16. We also found that the transcriptional regulation of this lipase is complex. Its basal expression and induction by germline stem cell arrest are modulated by multiple forkhead transcription factors and nuclear hormone receptors. These results suggest the existence of an endocrine axis from germline stem cells to fat storage tissue, which plays a vital role in regulation of somatic maintenance and longevity. This work is supported by Life Sciences Research Foundation and Ellison Medical Foundation fellowships.

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.

Sowa, Jessica et al. (2013) International Worm Meeting "Regulation of C. elegans Reproductive Aging by a Novel Gene-Environment Signaling Mechanism."

Wang, Meng, Sowa, Jessica

[International Worm Meeting, 2013]

Reproductive senescence is a hallmark of aging, the onset of which can be modulated by both genetic and environmental factors. However, the molecular mechanisms that integrate environmental and genetic signals to regulate the onset and progression of reproductive aging remain largely unknown. Here we report the first known instance of a gene-environment signaling mechanism functioning to regulate reproductive senescence in Caenorhabditis elegans. We found that C. elegans fed the standard lab diet of OP50 E. coli reproduce significantly longer than C. elegans fed the alternate diet of HB101 E. coli. This effect is mediated by the AWB olfactory neurons, which perceive a volatile odorant signal produced by HB101 E. coli. The presence or absence of this sensory cue specifically affects germline proliferation and maintenance, ultimately contributing to the timing of reproductive senescence. The effect of the HB101 odorant on reproductive span was found to be independent of all previously identified pathways for the regulation of reproductive aging in C. elegans, indicating that it acts through a novel regulatory mechanism. Furthermore, we have found that serotonin signaling plays a role as a downstream effector of this response. Together, these studies describe a previously unknown regulatory mechanism for reproductive senescence, and suggest the significance of gene-environment interactions in the regulation of reproductive aging.

Neve, Isaiah et al. (2015) International Worm Meeting "Modified OP50 E. coli expressing dsRNA elicite a robust RNA interference response in C. elegans."

Wang, Meng, Sowa, Jessica, Neve, Isaiah

[International Worm Meeting, 2015]

In the majority of research laboratories using C. elegans as a model, they sustain their animals on the B strain E. coli OP50. This strain is easy to manipulate in the laboratory, and has provided us with a key platform for defining many genetic pathways. Simultaneously, the series of revolutionary realizations which culminated in the 2006 Nobel Prize, quickly allowed the technique of dsRNA feeding to incite RNA interference (RNAi) to become a key technique in many laboratories. Two major resources are available to the RNAi wielding researcher, the Ahringer and Vidal libraries respectively. These libraries house thousands of E. coli clones with unique plasmids expressing dsRNA corresponding to individual C. elegans genes. Countless experimental insights have been facilitated using these resources. However, both libraries are housed in the HT115 E. coli K12 strain background. Several recent studies (Brooks et al., 2009; Soukas et al., 2009; Pang & Curran 2014) have revealed the importance of bacterial environment in eliciting certain genetically induced phenotypes. With the realization that gene-environment interactions may play a key role in the elucidation of genetic pathways, we have generated an OP50 strain capable of dependably housing and robustly expressing dsRNA plasmid vectors. Furthermore, when C. elegans are fed this OP50 strain, they activate a substantial RNAi response against the target gene of interest. We anticipate that this resource will allow the further characterization of gene-environment specific relationships. .

Sowa, Jessica et al. (2015) International Worm Meeting "Olfactory Regulation of C. elegans Reproductive Aging."

Wang, Meng, Mutlu, Ayse Sena, Sowa, Jessica

[International Worm Meeting, 2015]

As women age, they experience both a decline in fertility and an increased risk of miscarriage and birth defects. In addition to purely genetic contributions, reproductive aging is thought to be regulated by the complex interactions of genetic signaling pathways and environmental conditions. However, the molecular mechanisms integrating environmental and genetic signals to regulate reproductive aging remain unknown. Caenorhabditis elegans experience their diet of bacteria as a source of both metabolic and sensory input. We took advantage of this relationship as a convenient method of introducing environmental variation by raising C. elegans on different bacterial diets to investigate the effect of environment on reproductive aging. We found that C. elegans exposed to different bacterial environments show significant differences in the duration of their reproductive span. To further dissect the molecular mechanisms underlying these reproductive span differences we chose to focus on two strains of Escherichia coli (OP50 and HB101) that gave drastically different effects on C. elegans reproduction. We found that worms raised on OP50 reproduce longer and maintain their fertility later than worms raised on HB101. This effect is mediated by a pair of olfactory neurons which perceive a volatile odorant signal from the HB101 E.coli. The presence or absence of this environmental cue affects germline proliferation and maintenance in C. elegans, ultimately contributing to the timing of reproductive senescence. We have identified a pair of olfactory neurons, the AWB neurons,that are specifically required for this olfaction-mediated reproductive adaptation as well as for chemotaxis of C. elegans to the smell of the HB101 bacterial diet. Optogenetic activation of the AWB neurons confirmed that AWB activation was sufficient to induce reproductive span shortening in the absence of HB101. Finally, we identified neuropeptide release as the mechanism of AWB neurotransmission in response to the HB101 odorant. Together, our results reveal a novel pathway for the regulation of reproductive aging in C. elegans, and suggest the relevance of environment-sensitive signaling mechanisms in regulating the onset and progression of reproductive aging.

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.