de Voer G et al. (2008) Biochim Biophys Acta "Caenorhabditis elegans as a model for lysosomal storage disorders."

Taschner PE, De Voer G, Peters D

[Biochim Biophys Acta, 2008]

The nematode Caenorhabditis elegans is the simplest animal model available to study human disease. In this review, the worm homologues for the 58 human genes involved in lysosomal storage disorders and for 105 human genes associated with lysosomal function have been compiled. Most human genes had at least one worm homologue. In addition, the phenotypes of 147 mutants, in which these genes have been disrupted or knocked down, have been summarized and discussed. The phenotypic spectrum of worm models of lysosomal storage disorders varies from lethality to none obvious, with a large variety of intermediate phenotypes. The genetic power of C. elegans provides a means to identify genes involved in specific processes with relative ease. The overview of potential lysosomal phenotypes presented here might be used as a starting point for the phenotypic characterization of newly developed knock-out models or for the design of genetic screens selecting for loss or gain of suitable knock-out model phenotypes. Screens for genes involved in lysosomal biogenesis and function have been performed successfully resulting in the cup and glo mutants, but screens involving subtle phenotypes are likely to be difficult.

Guan K-L et al. (1999) Genes Dev "A G-protein signaling network mediated by an RGS protein."

Han M, Guan K-L

[Genes Dev, 1999]

A wide variety of extracellular stimuli induce signal transduction through receptors coupled to heterotrimeric G proteins, which consist of alpha, beta, and gamma subunits (Gilman 1987). The G alpha subunit has guanine nucleotide binding and GTP hydrolysis activities. Based on function and amino acid sequence homology, the Galpha, G alph i/o, G alpha q, and G alpha 12 (Simon et al. 1991; Hepler and Gilman 1992). As exemplified by the responsiveness of our five senses to environmental stimuli, signaling mediated by trimeric G proteins is often extremely rapid and transient. A key step in achieving such a raid response is the ability of the G alpha subunit to switch between it GDP- and GTP-bound forms. The nucleotide binding state of G alpha is regulated at both the GDP dissociation and GTP hydrolysis steps. Stimulation of receptors by agonists leads to a conformational change in the receptors which can function as a guanine nucleotide exchange factor to stimulate a rapid dissociation of GDP from the inactive G alpha. The nucleotide-free G alpha is then available to bind GTP, leading to the dissociation of G alpha from the G beta gamma heterodimer. Both the G alpha and G beat gamma subunits can interact with and regulate downstream effectors that include adenylyl cyclase, phospholipase C, and ion channels (Gilman 1987; Birnbaumer 1992).

Carol Bastiani et al. (2006) WormBook "Heterotrimeric G proteins in C. elegans."

Jane Mendel, Carol Bastiani

[WormBook, 2006]

Heterotrimeric G proteins, composed of alpha , beta , and gamma subunits, are able to transduce signals from membrane receptors to a wide variety of intracellular effectors. In this role, G proteins effectively function as dimers since the signal is communicated either by the G alpha subunit or the stable G betagamma complex. When inactive, G alpha -GDP associates with G betagamma and the cytoplasmic portion of the receptor. Ligand activation of the receptor stimulates an exchange of GTP for GDP resulting in the active signaling molecules G alpha -GTP and free G betagamma , either of which can interact with effectors. Hydrolysis of GTP restores G alpha -GDP, which then reassociates with G betagamma and receptor to terminate signaling. The rate of G protein activation can be enhanced by the guanine-nucleotide exchange factor, RIC-8 , while the rate of GTP hydrolysis can be enhanced by RGS proteins such as EGL-10 and EAT-16 . Evidence for a receptor-independent G-protein-signaling pathway has been demonstrated in C. elegans early embryogenesis. In this pathway, the G alpha subunits GOA-1 and GPA-16 are apparently activated by the non-transmembrane proteins GPR-1 , GPR-2 , and RIC-8 , and negatively regulated by RGS-7 . The C. elegans genome encodes 21 G alpha , 2 G beta and 2 G gamma subunits. The alpha subunits include one ortholog of each mammalian G alpha family: GSA-1 (Gs), GOA-1 (Gi/o), EGL-30 (Gq) and GPA-12 (G12). The remaining C. elegans alpha subunits ( GPA-1 , GPA-2 , GPA-3 , GPA-4 , GPA-5 , GPA-6 , GPA-7 , GPA-8 , GPA-9 , GPA-10 , GPA-11 , GPA-13 , GPA-14 , GPA-15 , GPA-16 , GPA-17 and ODR-3 ) are most similar to the Gi/o family, but do not share sufficient homology to allow classification. The conserved G alpha subunits, with the exception of GPA-12 , are expressed broadly while 14 of the new G alpha genes are expressed in subsets of chemosensory neurons. Consistent with their expression patterns, the conserved C. elegans alpha subunits, GSA-1 , GOA-1 and EGL-30 are involved in diverse and fundamental aspects of development and behavior. GOA-1 acts redundantly with GPA-16 in positioning of the mitotic spindle in early embryos. EGL-30 and GSA-1 are required for viability starting from the first larval stage. In addition to their roles in development and behaviors such as egg laying and locomotion, the EGL-30 , GSA-1 and GOA-1 pathways interact in a network to regulate acetylcholine release by the ventral cord motor neurons. EGL-30 provides the core signals for vesicle release, GOA-1 negatively regulates the EGL-30 pathway, and GSA-1 modulates this pathway, perhaps by providing positional cues. Constitutively activated GPA-12 affects pharyngeal pumping. The G alpha subunits unique to C. elegans are primarily involved in chemosensation. The G beta subunit, GPB-1 , as well as the G gamma subunit, GPC-2 , appear to function along with the alpha subunits in the classic G protein heterotrimer. The remaining G beta subunit, GPB-2 , is thought to regulate the function of certain RGS proteins, while the remaining G gamma subunit, GPC-1 , has a restricted role in chemosensation. The functional difference for most G protein pathways in C. elegans, therefore, resides in the alpha subunit. Many cells in C. elegans express multiple G alpha subunits, and multiple G protein pathways are known to function in specific cell types. For example, Go, Gq and Gs-mediated signaling occurs in the ventral cord motor neurons. Similarly, certain amphid neurons use multiple G protein pathways to both positively and negatively regulate chemosensation. C. elegans thus provides a powerful model for the study of interactions between and regulation of G protein signaling.

Porter MY et al. (2009) Prog Mol Biol Transl Sci "Insights into RGS protein function from studies in Caenorhabditis elegans."

Koelle MR, Porter MY

[Prog Mol Biol Transl Sci, 2009]

The nematode worm, Caenorhabditis elegans, contains orthologs of most regulator of G protein signaling (RGS) protein subfamilies and all four G protein -subunit subfamilies found in mammals. Every C. elegans RGS and G gene has been knocked out, and the in vivo functions and G targets of a number of RGS proteins have been characterized in detail. This has revealed a complex relationship between the RGS and G proteins, in which multiple RGS proteins can regulate the same G protein, either by acting redundantly or by exerting control over signaling under different circumstances or in different cells. RGS proteins that are coexpressed can also show specificity for distinct G targets in vivo, and the determinants of such specificity can reside outside of the RGS domain. This review will discuss how analysis in C. elegans may aid us in achieving a full understanding of the physiological functions of RGS proteins.

Phillips SN et al. (2006) Biochim Biophys Acta "Characterizing pathogenic processes in Batten disease: use of small eukaryotic model systems."

Muzaffar N, Phillips SN, Codlin S, Korey CA, Taschner PE, De Voer G, Pearce DA, Mole SE

[Biochim Biophys Acta, 2006]

The neuronal ceroid lipofuscinoses (NCLs) are neurodegenerative disorders. Nevertheless, small model organisms, including those lacking a nervous system, have proven invaluable in the study of mechanisms that underlie the disease and in studying the functions of the conserved proteins associated to each disease. From the single-celled yeast, Saccharomyces cerevisiae and Schizosaccharomyces pombe, to the worm, Caenorhabditis elegans and the fruitfly, Drosophila melanogaster, biochemical and, in particular, genetic studies on these organisms have provided insight into the NCLs.

Ebrahimi FAW et al. (1998) Curr Biol "Olfactory G proteins: Simple and complex signal transduction."

Ebrahimi FAW, Chess A

[Curr Biol, 1998]

In both vertebrates and invertebrates, olfactory perception is mediated by G-protein-coupled receptors. Recent work, in both mouse and Caenorhabditis elegans, sheds light on the role of specific G proteins in olfactory signal transduction, neuronal morphology and axon guidance.

Hinrichs MV et al. (2012) J Cell Biochem "Ric-8: different cellular roles for a heterotrimeric G-protein GEF."

Torrejon M, Montecino M, Hinrichs MV, Olate J

[J Cell Biochem, 2012]

Signaling via heterotrimeric G-proteins is evoked by agonist-mediated stimulation of seven transmembrane spanning receptors (GPCRs). During the last decade it has become apparent that G subunits can be activated by receptor-independent mechanisms. Ric-8 belongs to a highly conserved protein family that regulates heterotrimeric G-protein function, acting as a non-canonical guanine nucleotide exchange factors (GEF) over a subset of G subunits. In this review we discuss the roles of Ric-8 in the regulation of diverse cell functions, emphasizing the contribution of its multiple domain protein structure in these diverse functions.

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.

Matus D et al. (2018) J Dev Biol "G Proteins and GPCRs in C. elegans Development: A Story of Mutual Infidelity."

Promel S, Matus D

[J Dev Biol, 2018]

Many vital processes during C. elegans development, especially the establishment and maintenance of cell polarity in embryogenesis, are controlled by complex signaling pathways. G protein-coupled receptors (GPCRs), such as the four Frizzled family Wnt receptors, are linchpins in regulating and orchestrating several of these mechanisms. However, despite being GPCRs, which usually couple to G proteins, these receptors do not seem to activate classical heterotrimeric G protein-mediated signaling cascades. The view on signaling during embryogenesis is further complicated by the fact that heterotrimeric G proteins do play essential roles in cell polarity during embryogenesis, but their activity is modulated in a predominantly GPCR-independent manner via G protein regulators such as GEFs GAPs and GDIs. Further, the triggered downstream effectors are not typical. Only very few GPCR-dependent and G protein-mediated signaling pathways have been unambiguously defined in this context. This unusual and highly intriguing concept of separating GPCR function and G-protein activity, which is not restricted to embryogenesis in <i>C. elegans</i> but can also be found in other organisms, allows for essential and multi-faceted ways of regulating cellular communication and response. Although its relevance cannot be debated, its impact is still poorly discussed, and <i>C.</i><i>elegans</i> is an ideal model to understand the underlying principles.

Sigurbjornsdottir S et al. (2014) Nat Rev Mol Cell Biol "Molecular mechanisms of de novo lumen formation."

Mathew R, Sigurbjornsdottir S, Leptin M

[Nat Rev Mol Cell Biol, 2014]

Many organs contain networks of epithelial tubes that transport gases or fluids. A lumen can be generated by tissue that enwraps a pre-existing extracellular space or it can arise de novo either between cells or within a single cell in a position where there was no space previously. Apparently distinct mechanisms of de novo lumen formation observed in vitro - in three-dimensional cultures of endothelial and Madin-Darby canine kidney (MDCK) cells - and in vivo - in zebrafish vasculature, Caenorhabditis elegans excretory cells and the Drosophila melanogaster trachea - in fact share many common features. In all systems, lumen formation involves the structured expansion of the apical plasma membrane through general mechanisms of vesicle transport and of microtubule and actin cytoskeleton regulation.