Ruvkun G (2004) Endocrine Aspects of Successful Aging: Genes, Hormones and Lifestyles. Springer-Verlag, Berlin. "Regulation of C. elegans life span by insulin-like signaling."

Ruvkun G

[Endocrine Aspects of Successful Aging: Genes, Hormones and Lifestyles. Springer-Verlag, Berlin., 2004]

Finch CE et al. (2001) Annu Rev Genomics Hum Genet "The genetics of aging."

Ruvkun G, Finch CE

[Annu Rev Genomics Hum Genet, 2001]

The genetic analysis of life span has only begun in mammals, invertebrates, such as Caenorhabditis elegans and Drosophila, and yeast. Even at this primitive stage of the genetic analysis of aging, the physiological observations that rate of metabolism is intimately tied to life span is supported. In many examples from mice to worms to flies to yeast, genetic variants that affect life span also modify metabolism. Insulin signaling regulates life span coordinately with reproduction, metabolism, and free radical protective gene regulation in C. elegans. This may be related to the findings that caloric restriction also regulates mammalian aging, perhaps via the modulation of insulin-like signaling pathways. The nervous system has been implicated as a key tissue where insulin-like signaling and free radical protective pathways regulate life span in C. elegans and Drosophila. Genes that determine the life span could act in neuroendocrine cells in diverse animals. The involvement of insulin-like hormones suggests that the plasticity in life spans evident in animal phylogeny may be due to variation in the timing of release of hormones that control vitality and mortality as well as variation in the response to those hormones. Pedigree analysis of human aging may reveal variations in the orthologs of the insulin pathway genes and coupled pathways that regulate invertebrate aging. Thus, genetic approaches may identify a set of circuits that was established in ancestral metazoans to regulate their longevity.

Pasquinelli AE et al. (2002) Annu Rev Cell Dev Biol "Control of developmental timing by micrornas and their targets."

Ruvkun G, Pasquinelli AE

[Annu Rev Cell Dev Biol, 2002]

In Caenorhabditis elegans the timing of many developmental events is regulated by heterochronic genes. Such genes orchestrate the timing of cell divisions and fates appropriate for the developmental stage of an organism. Analyses of heterochronic mutations in the nematode C. elegans have revealed a genetic pathway that controls the timing of post-embryonic cell divisions and fates. Two of the genes in this pathway encode small regulatory RNAs. The 22 nucleotide (nt) RNAs downregulate the expression of protein-coding mRNAs of target heterochronic genes. Analogous variations in the timing of appearance of particular features have been noted among closely related species, suggesting that such explicit control of developmental timing may not be exclusive to C. elegans. In fact, some of the genes that globally pattern the temporal progression of C. elegans development, including one of the tiny RNA genes, are conserved and temporally regulated across much of animal phylogeny, suggesting that the molecular mechanisms of temporal control are ancient and universal. A very large family of tiny RNA genes called microRNAs, which are similar in structure to the heterochronic regulatory RNAs, have been detected in diverse animal species and are likely to be present in most metazoans. Functions of the newly discovered microRNAs are not yet known. Other examples of temporal programs during growth include the exquisitely choreographed temporal sequences of developmental fates in neurogenesis in Drosophila and the sequential programs of epidermal coloration in insect wing patterning. An interesting possibility is that microRNAs mediate transitions on a variety of time scales to pattern the activities of particular target protein-coding genes and in turn generate sets of cells over a period of time. Plasticity in these microRNA genes or their targets may lead to changes in relative developmental timing between related species, or heterochronic change. Instead of inventing new gene functions, even subtle changes in temporal expression of pre-existing control genes can result in speciation by altering the time at which they function.

Shore DE et al. (2013) Trends Cell Biol "A cytoprotective perspective on longevity regulation."

Shore DE, Ruvkun G

[Trends Cell Biol, 2013]

There are many mechanisms of lifespan extension, including the disruption of insulin/insulin-like growth factor 1 (IGF-1) signaling, metabolism, translation, and feeding. Despite the disparate functions of these pathways, inhibition of each induces responses that buffer stress and damage. Here, emphasizing data from genetic analyses in Caenorhabditis elegans, we explore the effectors and upstream regulatory components of numerous cytoprotective mechanisms activated as major elements of longevity programs, including detoxification, innate immunity, proteostasis, and oxidative stress response. We show that their induction underpins longevity extension across functionally diverse triggers and across species. Intertwined with the evolution of longevity, cytoprotective pathways are coupled to the surveillance of core cellular components, with important implications in normal and aberrant responses to drugs, chemicals, and pathogens.

Ruvkun GB et al. (1998) Science "The taxonomy of developmental control in Caenorhabditis elegans."

Ruvkun GB, Hobert O

[Science, 1998]

The Caenorhabditis elegans genome sequence was surveyed for transcription factor and signaling gene families that have been shown to regulate development in a variety of species. About 10 to 25 percent of the genes in most of the gene families already have been genetically analyzed in C. elegans, about half of the genes detect probable orthologs in other species, and about 10 to 25 percent of the genes are, at present, unique to C. elegans. Caenorhabditis elegans is also missing genes that are found in vertebrates and other invertebrates. Thus the genome sequence reveals universals in developmental control that are the legacy of metazoan complexity before the Cambrian explosion, as well as genes that have been more recently invented or lost in particular phylogenetic lineages.AD - Department of Molecular Biology, Massachusetts General Hospital, Department of Genetics, Harvard Medical School, Boston, MA 02114, USA. ruvkun@frodo.mgh.harvard.eduFAU - Ruvkun, GAU - Ruvkun GFAU - Hobert, OAU - Hobert OLA - engPT - Journal ArticlePT - ReviewPT - Review, TutorialCY - UNITED STATESTA - ScienceJID - 0404511RN - 0 (Helminth Proteins)RN - 0 (Transcription Factors)SB - IM

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.

Wade N (1997) The New York Times "A worm and a computer help illuminate diabetes."

Wade N

[The New York Times, 1997]

His tall figure bent over a computer screen in his laboratory at the Massachusetts General Hospital, Dr. Gary Ruvkun rummages through a distant genetic data base for matches to a gene he believes is involved in diabetes. ?You learn how to read these as they are ratcheting by,? he says, while lines of data streak up his screen. ?I think MTV is good training.?

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.