Wang J et al. (2024) Genetics "Extracellular vesicles."

Barr MM, Wehman AM, Wang J

[Genetics, 2024]

Extracellular vesicles (EVs) encompass a diverse array of membrane-bound organelles released outside cells in response to developmental and physiological cell needs. EVs play important roles in remodeling the shape and content of differentiating cells and can rescue damaged cells from toxic or dysfunctional content. EVs can send signals and transfer metabolites between tissues and organisms to regulate development, respond to stress or tissue damage, or alter mating behaviors. While many EV functions have been uncovered by characterizing ex vivo EVs isolated from body fluids and cultured cells, research using the nematode Caenorhabditis elegans has provided insights into the in vivo functions, biogenesis, and uptake pathways. The C. elegans EV field has also developed methods to analyze endogenous EVs within the organismal context of development and adult physiology in free-living, behaving animals. In this review, we summarize major themes that have emerged for C. elegans EVs and their relevance to human health and disease. We also highlight the diversity of biogenesis mechanisms, locations, and functions of worm EVs and discuss open questions and unexplored topics tenable in C. elegans, given the nematode model is ideal for light and electron microscopy, genetic screens, genome engineering, and high-throughput omics.

Wang J et al. (2016) Cell Mol Neurobiol "Ciliary Extracellular Vesicles: Txt Msg Organelles."

Barr MM, Wang J

[Cell Mol Neurobiol, 2016]

Cilia are sensory organelles that protrude from cell surfaces to monitor the surrounding environment. In addition to its role as sensory receiver, the cilium also releases extracellular vesicles (EVs). The release of sub-micron sized EVs is a conserved form of intercellular communication used by all three kingdoms of life. These extracellular organelles play important roles in both short and long range signaling between donor and target cells and may coordinate systemic responses within an organism in normal and diseased states. EV shedding from ciliated cells and EV-cilia interactions are evolutionarily conserved phenomena, yet remarkably little is known about the relationship between the cilia and EVs and the fundamental biology of EVs. Studies in the model organisms Chlamydomonas and Caenorhabditis elegans have begun to shed light on ciliary EVs. Chlamydomonas EVs are shed from tips of flagella and are bioactive. Caenorhabditis elegans EVs are shed and released by ciliated sensory neurons in an intraflagellar transport-dependent manner. Caenorhabditis elegans EVs play a role in modulating animal-to-animal communication, and this EV bioactivity is dependent on EV cargo content. Some ciliary pathologies, or ciliopathies, are associated with abnormal EV shedding or with abnormal cilia-EV interactions. Until the 21st century, both cilia and EVs were ignored as vestigial or cellular junk. As research interest in these two organelles continues to gain momentum, we envision a new field of cell biology emerging. Here, we propose that the cilium is a dedicated organelle for EV biogenesis and EV reception. We will also discuss possible mechanisms by which EVs exert bioactivity and explain how what is learned in model organisms regarding EV biogenesis and function may provide insight to human ciliopathies.

Wang J et al. (2018) Essays Biochem "Cell-cell communication via ciliary extracellular vesicles: clues from model systems."

Barr MM, Wang J

[Essays Biochem, 2018]

In this short review, we will focus on the uniqueness of ciliary extracellular vesicles (EVs). In particular, we will review what has been learned regarding EVs produced by cilia of model organisms. Model systems including <i>Chlamydomonas, Caenorhabditis elegans</i>, and mouse revealed the fundamental biology of cilia and flagella and provide a paradigm to understand the roles of cilia and flagella in human development, health, and disease. Likewise, we propose that general principles learned from model systems regarding ciliary EV biogenesis and functions may provide a framework to explore the roles of ciliary EVs in human development, health, and disease.

Wang ZW (2010) J Neurosci Res "Origin of quantal size variation and high-frequency miniature postsynaptic currents at the Caenorhabditis elegans neuromuscular junction."

Wang ZW

[J Neurosci Res, 2010]

The neuromuscular junction (NMJ) of Caenorhabditis elegans has proved to be a very useful model synapse for investigating molecular mechanisms of synaptic transmission. Intriguingly, miniature postsynaptic currents (minis) at this synapse occur at an unusually high frequency (50-90 Hz in wild-type worms) and show large variation in quantal size (from &lt;10 pA to &gt;200 pA). It is important to understand the cellular and molecular bases for these properties of minis in order to interpret electrophysiological data from this synapse properly. Existing data suggest that several factors may contribute to the high frequency and quantal size variation, including 1) the establishment of multiple NMJs with each body-wall muscle cell, 2) diversity of postsynaptic receptors (two acetylcholine receptors and one GABA receptor), 3) association of one presynaptic site with several body-wall muscle cells, 4) effects of Ca(2+) at the presynaptic site, and 5) a possibly elevated (less negative) resting membrane potential in motoneurons. Neither the frequency nor the quantal size of minis is affected by electrical coupling of body-wall muscle cells. Furthermore, quantal size variation is not due to synchronized multivesicular release. Analyses of the C. elegans NMJ may lead to a better understanding of the mechanisms controlling the frequency and quantal size of minis of other synapses as well.

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 YC et al. (2012) FEBS J "Evolutionarily conserved protein arginine methyltransferases in non-mammalian animal systems."

Li C, Wang YC

[FEBS J, 2012]

Protein arginine methylation is catalyzed by members of the protein arginine methyltransferase (PRMT) family. In the present review, nine PRMTs identified in mammals (human) were used as templates to survey homologous PRMTs in 10 animal species with a completed sequence available in non-mammalian vertebrates, invertebrate chordates, echinoderms, arthropods, nematodes and cnidarians. We show the conservation of the most typical type I PRMT1 and type II PRMT5 in all of the species examined, the wide yet different distribution of PRMT3, 4 and 7 in non-mammalian animals, the vertebrate-restricted distribution of PRMT8 and the special reptile/avian-deficient distribution of PRMT2 and 6. We summarize the basic functions of each PRMT and focus on the current investigations of PRMTs in the non-mammalian animal models, including Xenopus, fish (zebrafish, flounder and medaka), Drosophila and Caenorhabditis elegans. Studies in the model systems not only complement the understanding of the functions of PRMTs in mammals, but also provide valuable information about their evolution, as well as their critical roles and interplays.

Wang Y et al. (2013) FEBS J "Engineered proteins with Pumilio/fem-3 mRNA binding factor scaffold to manipulate RNA metabolism."

Wang Z, Tanaka Hall TM, Wang Y

[FEBS J, 2013]

Pumilio/fem-3 mRNA binding factor proteins are characterized by a sequence-specific RNA-binding domain. This unique single-stranded RNA recognition module, whose sequence specificity can be reprogrammed, has been fused with functional modules to engineer protein factors with various functions. We summarize the advances made with respect to developing RNA regulatory tools, as well as opportunities for the future.

Wang M et al. (2018) Int J Mol Sci "The PUF Protein Family: Overview on PUF RNA Targets, Biological Functions, and Post Transcriptional Regulation."

Wang M, Sakr S, Oge L, Hamama L, Perez-Garcia MD

[Int J Mol Sci, 2018]

Post-transcriptional regulation of gene expression plays a crucial role in many processes. In cells, it is mediated by diverse RNA-binding proteins. These proteins can influence mRNA stability, translation, and localization. The PUF protein family (Pumilio and FBF) is composed of RNA-binding proteins highly conserved among most eukaryotic organisms. Previous investigations indicated that they could be involved in many processes by binding corresponding motifs in the 3'UTR or by interacting with other proteins. To date, most of the investigations on PUF proteins have been focused on Caenorhabditis elegans, Drosophila melanogaster, and Saccharomyces cerevisiae, while only a few have been conducted on Arabidopsis thaliana. The present article provides an overview of the PUF protein family. It addresses their RNA-binding motifs, biological functions, and post-transcriptional control mechanisms in Caenorhabditis elegans, Drosophila melanogaster, Saccharomyces cerevisiae, and Arabidopsis thaliana. These items of knowledge open onto new investigations into the relevance of PUF proteins in specific plant developmental processes.

O'Hagan R et al. (2014) Semin Cell Dev Biol "Mating behavior, male sensory cilia, and polycystins in Caenorhabditis elegans."

Barr MM, O'Hagan R, Wang J

[Semin Cell Dev Biol, 2014]

The investigation of Caenorhabditis elegans males and the male-specific sensory neurons required for mating behaviors has provided insight into the molecular function of polycystins and mechanisms that are needed for polycystin ciliary localization. In humans, polycystin 1 and polycystin 2 are needed for kidney function; loss of polycystin function leads to autosomal dominant polycystic kidney disease (ADPKD). Polycystins localize to cilia in C. elegans and mammals, a finding that has guided research into ADPKD. The discovery that the polycystins form ciliary receptors in male-specific neurons needed for mating behaviors has also helped to unlock insights into two additional exciting new areas: the secretion of extracellular vesicles; and mechanisms of ciliary specialization. First, we will summarize the studies done in C. elegans regarding the expression, localization, and function of the polycystin 1 and 2 homologs, LOV-1 and PKD-2, and discuss insights gained from this basic research. Molecules that are co-expressed with the polycystins in the male-specific neurons may identify evolutionarily conserved molecular mechanisms for polycystin function and localization. We will discuss the finding that polycystins are secreted in extracellular vesicles that evoke behavioral change in males, suggesting that such vesicles provide a novel form of communication to conspecifics in the environment. In humans, polycystin-containing extracellular vesicles are secreted in urine and can be taken up by cilia, and quickly internalized. Therefore, communication by polycystin-containing extracellular vesicles may also use mechanisms that are evolutionarily conserved from nematode to human. Lastly, different cilia display structural and functional differences that specialize them for particular tasks, despite the fact that virtually all cilia are built by a conserved intraflagellar transport (IFT) mechanism and share some basic structural features. Comparative analysis of the male-specific cilia with the well-studied cilia of the amphid and phasmid neurons has allowed identification of molecules that specialize the male cilia. We will discuss the molecules that shape the male-specific cilia. The cell biology of cilia in male-specific neurons demonstrates that C. elegans can provide an excellent model of ciliary specialization.

Felix MA et al. (2002) Hermann, Editeurs des Sciences et des Arts. Paris, France. "Caenorhabditis elegans. Un organisme modele en biologie."

Labouesse M, Segalat L, Felix MA

[Hermann, Editeurs des Sciences et des Arts. Paris, France., 2002]

L'espce Caenorhabditis elegans fut dcrite en 1900 Alger par E. Maupas, qui s'intressait son mode de reproduction hermaphrodite. Plus tard, vers le milieu du vingtime sicle, V. Nigon et ses collaboratuers Lyon tudirent les reorganizations cellulaires accompagnant la fecundation et les premiers clivages. J. Brun isola les preiers mutants morpholgiques.