Wang Z et al. (2011) Methods Cell Biol "Dissection of genetic pathways in C. elegans."

Sherwood DR, Wang Z

[Methods Cell Biol, 2011]

With unique genetic and cell biological strengths, C. elegans has emerged as a powerful model system for studying many biological processes. These processes are typically regulated by complex genetic networks consisting of genes. Identifying those genes and organizing them into genetic pathways are two major steps toward understanding the mechanisms that regulate biological events. Forward genetic screens with various designs are a traditional approach for identifying candidate genes. The completion of the genome sequencing in C. elegans and the advent of high-throughput experimental techniques have led to the development of two additional powerful approaches: functional genomics and systems biology. Genes that are discovered by these approaches can be ordered into interacting pathways through a variety of strategies, involving genetics, cell biology, biochemistry, and functional genomics, to gain a more complete understanding of how gene regulatory networks control a particular biological process. The aim of this review is to provide an overview of the approaches available to identify and construct the genetic pathways using C. elegans.

Wang Z et al. (2011) Curr Opin Neurobiol "Genetic dissection of axon regeneration."

Jin Y, Wang Z

[Curr Opin Neurobiol, 2011]

Axon regeneration has long been studied in vertebrate model organisms and neuronal cultures. Recent development of axon regeneration paradigms in genetic model organisms, such as Caenorhabditis elegans, Drosophila and zebrafish, has opened an exciting field for in vivo functional dissection of regeneration pathways. Studies in these organisms have discovered essential genes and pathways for axon regrowth. The conservation of these genes crossing animal phyla suggests mechanistic relevance to higher organisms. The power of genetic approaches in these organisms makes large-scale genetic and pharmacological screens feasible and can greatly accelerate the mechanistic understanding of axon regeneration.

Wang Z (2024) Methods Mol Biol "Caenorhabditis elegans as an In Vivo Model Organism to Elucidate Teratogenic Effects."

Wang Z

[Methods Mol Biol, 2024]

Exogenous teratogens contribute to approximately 10% of the human abnormality with exposure occurrence during the prenatal and fetal period. However, the assessment methods and underlying mechanism remain unclear. The nematode Caenorhabditis elegans has been recognized as one of the ideal model animals for toxicologic research as convenient culture, low cost, and complete phenotypes and genomic profiling. This chapter describes the protocols about the estimations on the teratogenic effects using nematodes as model organisms, including the growth, development, behavior, reproduction, energy balance, and transgenes.

Wang Z et al. (2017) J Clin Invest "Nuclear receptors: emerging drug targets for parasitic diseases."

Schaffer NE, Wang Z, Kliewer SA, Mangelsdorf DJ

[J Clin Invest, 2017]

Parasitic worms infect billions of people worldwide. Current treatments rely on a small group of drugs that have been used for decades. A shortcoming of these drugs is their inability to target the intractable infectious stage of the parasite. As well-known therapeutic targets in mammals, nuclear receptors have begun to be studied in parasitic worms, where they are widely distributed and play key roles in governing metabolic and developmental transcriptional networks. One such nuclear receptor is DAF-12, which is required for normal nematode development, including the all-important infectious stage. Here we review the emerging literature that implicates DAF-12 and potentially other nuclear receptors as novel anthelmintic targets.

Wang Z et al. (2010) BMC Genomics "Characterizing Ancylostoma caninum transcriptome and exploring nematode parasitic adaptation."

Martin J, Wang Z, Hawdon J, Mitreva M, Wilson RK, Abubucker S

[BMC Genomics, 2010]

BACKGROUND: Hookworm infection is one of the most important neglected diseases in developing countries, with approximately 1 billion people infected worldwide. To better understand hookworm biology and nematode parasitism, the present study generated a near complete transcriptome of the canine hookworm Ancylostoma caninum to a very high coverage using high throughput technology, and compared it to those of the free-living nematode Caenorhabditis elegans and the parasite Brugia malayi. RESULTS: The generated transcripts from four developmental stages, infective L3, serum stimulated L3, adult male and adult female, covered 93% of the A. caninum transcriptome. The broad diversity among nematode transcriptomes was confirmed, and an impact of parasitic adaptation on transcriptome diversity was inferred. Intra-population analysis showed that A. caninum has higher coding sequence diversity than humans. Examining the developmental expression profiles of A. caninum revealed major transitions in gene expression from larval stages to adult. Adult males expressed the highest number of selectively expressed genes, but adult female expressed the highest number of selective parasitism-related genes. Genes related to parasitism adaptation and A. caninum specific genes exhibited more expression selectivity while those conserved in nematodes tend to be consistently expressed. Parasitism related genes were expressed more selectively in adult male and female worms. The comprehensive analysis of digital expression profiles along with transcriptome comparisons enabled identification of a set of parasitism genes encoding secretory proteins in animal parasitic nematode. CONCLUSIONS: This study validated the usage of deep sequencing for gene expression profiling. Parasitic adaptation of the canine hookworm is related to its diversity and developmental dynamics. This comprehensive comparative genomic and expression study substantially improves our understanding of the basic biology and parasitism of hookworms and, is expected, in the long run, to accelerate research toward development of vaccines and novel anthelmintics.

Wang Z et al. (2018) Bioinformatics "Deep Reinforcement Learning of Cell Movement in the Early Stage of C. elegans Embryogenesis."

Li H, Xu Y, Bao Z, Li C, Wang Z, Wang D

[Bioinformatics, 2018]

Motivation: Cell movement in the early phase of C. elegans development is regulated by a highly complex process in which a set of rules and connections are formulated at distinct scales. Previous efforts have demonstrated that agent-based, multi-scale modeling systems can integrate physical and biological rules and provide new avenues to study developmental systems. However, the application of these systems to model cell movement is still challenging and requires a comprehensive understanding of regulatory networks at the right scales. Recent developments in deep learning and reinforcement learning provide an unprecedented opportunity to explore cell movement using 3D time-lapse microscopy images. Results: We present a deep reinforcement learning approach within an agent-based modeling system to characterize cell movement in the embryonic development of C. elegans. Our modeling system captures the complexity of cell movement patterns in the embryo and overcomes the local optimization problem encountered by traditional rule-based, agent-based modeling that uses greedy algorithms. We tested our model with two real developmental processes: the anterior movement of the Cpaaa cell via intercalation and the rearrangement of the superficial left-right asymmetry. In the first case, the model results suggested that Cpaaa's intercalation is an active directional cell movement caused by the continuous effects from a longer distance (farther than the length of two adjacent cells), as opposed to a passive movement caused by neighbor cell movements. In the second case, a leader-follower mechanism well explained the collective cell movement pattern in the asymmetry rearrangement. These results showed that our approach to introduce deep reinforcement learning into agent-based modeling can test regulatory mechanisms by exploring cell migration paths in a reverse engineering perspective. This model opens new doors to explore the large datasets generated by live imaging. Availability: Source code is available at https://github.com/zwang84/drl4cellmovement. Contact: dwang7@utk.edu, baoz@mskcc.org. Supplementary information: Supplementary data are available at Bioinformatics online.

Wang Z et al. (2023) Nat Commun "ACS-20/FATP4 mediates the anti-ageing effect of dietary restriction in C. elegans."

Zang X, Zhang S, Wu Z, Zou L, Wu D, Zhu M, Wang Z, Zhu H, Zhang Y, Wang Q, Lan J, Zhang H, Chen D

[Nat Commun, 2023]

Dietary restriction is an effective anti-ageing intervention across species. However, the molecular mechanisms from the metabolic aspects of view are still underexplored. Here we show ACS-20 as a key mediator of dietary restriction on healthy ageing from a genetic screen of the C. elegans acyl-CoA synthetase family. ACS-20 functions in the epidermis during development to regulate dietary restriction-induced longevity. Functional transcriptomics studies reveal that elevated expression of PTR-8/Patched is responsible for the proteostasis and lifespan defects of acs-20. Furthermore, the conserved NHR-23 nuclear receptor serves as a transcriptional repressor of ptr-8 and a key regulator of dietary restriction-induced longevity. Mechanistically, a specific region in the ptr-8 promoter plays a key role in mediating the transcription regulation and lifespan extension under dietary restriction. Altogether, these findings identify a highly conserved lipid metabolism enzyme as a key mediator of dietary restriction-induced lifespan and healthspan extension and reveal the downstream transcriptional regulation mechanisms.

Wang Z et al. (2024) Geroscience "Cannabinoids and healthy ageing: the potential for extending healthspan and lifespan in preclinical models with an emphasis on Caenorhabditis elegans."

Wang Z, Arnold JC

[Geroscience, 2024]

There is a significant global upsurge in the number and proportion of older persons in the population. With this comes an increasing prevalence of age-related conditions which pose a major challenge to healthcare systems. The development of anti-ageing treatments may help meet this challenge by targeting the ageing process which is a common denominator to many health problems. Cannabis-like compounds (cannabinoids) are reported to improve quality of life and general well-being in human trials, and there is increasing preclinical research highlighting that they have anti-ageing activity. Moreover, preclinical evidence suggests that endogenous cannabinoids regulate ageing processes. Here, we review the anti-ageing effects of the cannabinoids in various model systems, including the most extensively studied nematode model, Caenorhabditis elegans. These studies highlight that the cannabinoids lengthen healthspan and lifespan, with emerging evidence that they may also hinder the development of cellular senescence. The non-psychoactive cannabinoid cannabidiol (CBD) shows particular promise, with mechanistic studies demonstrating it may work through autophagy induction and activation of antioxidative systems. Furthermore, CBD improves healthspan parameters such as diminishing age-related behavioural dysfunction in models of both healthy and accelerated ageing. Translation into mammalian systems provides an important next step. Moreover, looking beyond CBD, future studies could probe the multitude of other cannabis constituents for their anti-ageing activity.

Wang, Z. et al. (2009) International Worm Meeting "A conserved SWIM domain protein regulates axon guidance in C. elegans."

Hou, Y., Jin, Y., Wang, Z., Wu, Z., Chisholm, A.D.

[International Worm Meeting, 2009]

We are interested in the molecular pathways that guide axon outgrowth during development and in adults. We will report our analysis of the role of PQN-55 (prion-like-Q/N-rich-domain-bearing protein 55), a member of a conserved novel protein family (see the abstract by Hou et al, 2007 International Worm Meeting), in axon guidance and regeneration in C. elegans. This protein family contain an N-terminal SWIM domain, followed by four domains conserved among the family members. The SWIM domain is defined by its characteristic Zinc-binding CxCxnCxH sequence, and has been linked to transcriptional regulation and several signal transduction pathways. Ppqn-55-GFP reporters are expressed widely in neurons, epithelial cells, and muscles from early embryogenesis onward. Analysis of the localization of functional GFP-tagged PQN-55 in neurons suggests PQN-55 may be associated with endosomes. pqn-55 loss-of-function mutants are overall healthy but show mild abnormalities in egg-laying behavior and locomotion. Axon guidance is generally normal in these mutants. However, we observed that some AVM touch neurons display impaired ventral axon guidance. The ventral projection of AVM is known to be under the control of the repellent SLT-1/SAX-3 pathway and the attractive UNC-6/UNC-40 pathway. Interrupting either pathway causes ventral guidance defects of AVM axons. We are currently determining whether PQN-55 functions in one of these known guidance pathways. We will also report our studies on the role of PQN-55 in adult axon regeneration.

Wang Z et al. (2022) Nat Mach Intell "Hierarchical deep reinforcement learning reveals novel mechanism of cell movement."

Bao Z, Yang J, Wang D, Wang Z, Xu Y

[Nat Mach Intell, 2022]

Time-lapse images of cells and tissues contain rich information of dynamic cell behaviors, which reflect the underlying processes of proliferation, differentiation and morphogenesis. However, we lack computational tools for effective inference. Here, we exploit Deep Reinforcement Learning (DRL) to infer cell-cell interactions and collective cell behaviors in tissue morphogenesis from 3D, time-lapse images. We used Hierarchical DRL (HDRL), known for multiscale learning and data efficiency, to examine cell migrations based on images with ubiquitous nuclear label and simple rules formulated from empirical statistics of the images. When applied to C. elegans embryogenesis, HDRL reveals a multi-phase, modular organization of cell movement. Imaging with additional cellular markers confirms the modular organization as a novel migration mechanism, which we term sequential rosettes. Furthermore, HDRL forms a transferable model that successfully differentiates sequential rosettes-based migration from others. Our study demonstrates a powerful approach to infer the underlying biology from time-lapse imaging without prior knowledge.