Francesconi M et al. (2014) Nature "The effects of genetic variation on gene expression dynamics during development."

Lehner B, Francesconi M

[Nature, 2014]

The development of a multicellular organism and physiological responses require massive coordinated changes in gene expression across several cell and tissue types. Polymorphic regions of the genome that influence gene expression levels have been identified by expression quantitative trait locus (eQTL) mapping in many species, including loci that have cell-dependent, tissue-dependent and age-dependent effects. However, there has been no comprehensive characterization of how polymorphisms influence the complex dynamic patterns of gene expression that occur during development and in physiology. Here we describe an efficient experimental design to infer gene expression dynamics from single expression profiles in different genotypes, and apply it to characterize the effect of local (cis) and distant (trans) genetic variation on gene expression at high temporal resolution throughout a 12-hour period of the development of Caenorhabditis elegans. Taking dynamic variation into account identifies >50% more cis-eQTLs, including more than 900 that alter the dynamics of expression during this period. Local sequence polymorphisms extensively affect the timing, rate, magnitude and shape of expression changes. Indeed, many local sequence variants both increase and decrease gene expression, depending on the time-point profiled. Expression dynamics during this 12-hour period are also influenced extensively in trans by distal loci. In particular, several trans loci influence genes with quite diverse dynamic expression patterns, but they do so primarily during a common time interval. Trans loci can therefore act as modifiers of expression during a particular period of development. This study provides the first characterization, to our knowledge, of the effect of local and distant genetic variation on the dynamics of gene expression throughout an extensive time period. Moreover, the approach developed here should facilitate the genetic dissection of other dynamic processes, including potentially development, physiology and disease progression in humans.

Waszak SM et al. (2013) Dev Cell "Rounding up natural gene expression variation during development."

Waszak SM, Deplancke B

[Dev Cell, 2013]

Molecular insights into the genetic control of development have been mainly derived from single gene mutant studies. Francesconi and Lehner (2013) report now in Nature a genome-wide map of natural sequence variants that affect the temporal expression dynamics of thousands of genes during development of the roundworm Caenorhabditis elegans.

Ishihara T et al. (1997) International C. elegans Meeting "METABOTROPIC GLUTAMATE RECEPTORS IN C. ELEGANS"

Francesconi A, Katsura I, Ishihara T, Duvoisin RM

[International C. elegans Meeting, 1997]

Glutamate receptors are classified into ionotropic receptors and metabotropic receptors (mGluRs). mGluRs, which couple with G-proteins, are divided into three subgroups. The receptors in the first subgroup are coupled to Gq and the IP3/Ca2+ signal transduction system, while the other receptors are involved in inhibiting cAMP formation through Gi. By studying the knockout mice lacking the mGluR gene, it was shown that the mGluRs are involved in higher order functions in mammalian nervous systems, as well as in neural network formation. In the C. elegans genome project, two mGluR genes (mgl-1, mgl-2) have been identified. The predicted amino acid sequences show MGL-1 belongs to the Gi coupled mGluR group, while MGL-2 belongs to the Gq coupled group. Indeed, we found that the HEK293 cells expressing the mgl-2 cDNA increase in phosphoinostitol turnover, responding to glutamate. To elucidate the expression pattern of the C. elegans mGluR genes, we generated transgenic worms carrying a chimeric mGluR-GFP fusion gene. The fusion gene of mgl-2 is expressed essentially in interneurons, while that of mgl-1 is expressed in motorneurons and pharyngeal neurons as well as interneurons. To elucidate functions of mGluRs in C. elegans, we isolated mutants of mGluR genes by the Tc1 insertion/ deletion strategy. We examined various behavioral analyses of them. It seems that the mgl-2 mutant shows abnormal head movement and stronger tap reversal reflexes. We are testing whether these abnormalities can be rescued by the wild type mgl-2 gene.

Gal, C et al. (2015) International Worm Meeting "Regulation of gene expression by the DREAM complex."

Latorre, I, Appert, A, Chesney, M, Ahringer, J, Gal, C

[International Worm Meeting, 2015]

The conserved eight subunit DREAM (DP, Retinoblastoma [Rb]-like, E2F, and MuvB) complex is a regulator of cell cycle and quiescence genes and plays an important role in development and disease. The C. elegans DREAM members are LIN-35/Rb-like, EFL-1/E2F, DPL-1/DP1, LIN-8, LIN-37, LIN-52, LIN-53, and LIN-54. Recent work has demonstrated that C. elegans direct DREAM targets are de-repressed in the absence of the Rb-like protein LIN-35 and that high gene body levels of the histone variant H2A.Z are linked with target repression1. However, the mechanism that generates gene body H2A.Z enrichment, and the relationship between DREAM and H2A.Z are not currently understood. Furthermore, the functions and regulatory interactions of individual complex members are not clear. For example, LIN-35 has been demonstrated to be a transcriptional repressor by a number of groups, whilst the DP and E2F proteins have previously been reported to act as activators of transcription2. In addition, mutants of individual DREAM complex members do not all have the same phenotype, indicating different functions. Therefore, we are investigating the contribution of DPL-1 (DP) and EFL-1 (E2F) to DREAM target gene repression. We are also carrying out a GFP reporter screen to identify additional components required for DREAM-mediated repression, to elucidate the mechanisms behind DREAM mediated developmental control.1. Latorre, I., Chesney, M.A., Garrigues, J.M., Stempor, P., Appert, A., Francesconi, M., Strome, S., and Ahringer, J. (2015) 'The DREAM complex promotes gene body H2A.Z for target repression', Genes Dev., 29, 495-5002. Chi, W & Reinke, V. (2006) 'Promotion of oogenesis and embryogenesis in the C. elegans gonad by EFL-1/DPL-1 (E2F) does not require LIN-35 (pRB)', Development, 133, 3147-57.

Quartey MO et al. (2021) Sci Rep "The A(1-38) peptide is a negative regulator of the A(1-42) peptide implicated in Alzheimer disease progression."

Pennington PR, Heistad RM, Nyarko JNK, Barnes JR, Bolanos MAC, Parsons MP, Knudsen KJ, De Carvalho CE, Leary SC, Mousseau DD, Buttigieg J, Maley JM, Quartey MO

[Sci Rep, 2021]

The pool of -Amyloid (A) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for A peptides. We examined how a naturally occurring variant, e.g. A(1-38), interacts with the AD-related variant, A(1-42), and the predominant physiological variant, A(1-40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that A(1-38) interacts differently with A(1-40) and A(1-42) and, in general, A(1-38) interferes with the conversion of A(1-42) to a -sheet-rich aggregate. Functionally, A(1-38) reverses the negative impact of A(1-42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an A(1-42) phenotype in Caenorhabditis elegans. A(1-38) also reverses any loss of MTT conversion induced by A(1-40) and A(1-42) in HT-22 hippocampal neurons and APOE 4-positive human fibroblasts, although the combination of A(1-38) and A(1-42) inhibits MTT conversion in APOE 4-negative fibroblasts. A greater ratio of soluble A(1-42)/A(1-38) [and A(1-42)/A(1-40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that A(1-38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant A(1-42).

Danielle Thierry-Mieg et al. (2003) Worm Breeder's Gazette "www.wormgenes.org , a new gene centered database"

Vahan Simonyan, Michel Potdevin, Mark Sienkiewicz, Yuji KOHARA, Jean Thierry-Mieg, Danielle Thierry-Mieg, Tadasu SHIN-I

[Worm Breeder's Gazette, 2003]

Wormgenes is a new resource for C.elegans offering a detailed summary about each gene and a powerful query system.

Tangrodchanapong T et al. (2020) Front Pharmacol "Frondoside A Attenuates Amyloid- Proteotoxicity in Transgenic Caenorhabditis elegans by Suppressing Its Formation."

Tangrodchanapong T, Sobhon P, Meemon K

[Front Pharmacol, 2020]

Oligomeric assembly of Amyloid- (A) is the main toxic species that contribute to early cognitive impairment in Alzheimer's patients. Therefore, drugs that reduce the formation of A oligomers could halt the disease progression. In this study, by using transgenic <i>Caenorhabditis elegans</i> model of Alzheimer's disease, we investigated the effects of frondoside A, a well-known sea cucumber <i>Cucumaria frondosa</i> saponin with anti-cancer activity, on A aggregation and proteotoxicity. The results showed that frondoside A at a low concentration of 1 M significantly delayed the worm paralysis caused by A aggregation as compared with control group. In addition, the number of A plaque deposits in transgenic worm tissues was significantly decreased. Frondoside A was more effective in these activities than ginsenoside-Rg3, a comparable ginseng saponin. Immunoblot analysis revealed that the level of small oligomers as well as various high molecular weights of A species in the transgenic <i>C. elegans</i> were significantly reduced upon treatment with frondoside A, whereas the level of A monomers was not altered. This suggested that frondoside A may primarily reduce the level of small oligomeric forms, the most toxic species of A. Frondoside A also protected the worms from oxidative stress and rescued chemotaxis dysfunction in a transgenic strain whose neurons express A. Taken together, these data suggested that low dose of frondoside A could protect against A-induced toxicity by primarily suppressing the formation of A oligomers. Thus, the molecular mechanism of how frondoside A exerts its anti-A aggregation should be studied and elucidated in the future.

Hodgkin JA (1998) International Journal of Developmental Biology "Seven types of pleiotropy."

Hodgkin JA

[International Journal of Developmental Biology, 1998]

Pleiotropy , a situation in which a single gene influences multiple phenotypic tra its, can arise in a variety of ways. This paper discusses possible underlying mechanisms and proposes a classification of the various phenomena involved.

Tuck S (2011) Curr Biol "Extracellular vesicles: budding regulated by a phosphatidylethanolamine translocase."

Tuck S

[Curr Biol, 2011]

Recent work on a Caenorhabditis elegans transmembrane ATPase reveals a central role for the aminophospholipid phosphatidylethanolamine in the production of a class of extracellular vesicles.

Viney ME et al. (2004) Naturwissenschaften "Is dauer pheromone of Caenorhabditis elegans really a pheromone?"

Viney ME, Franks NR

[Naturwissenschaften, 2004]

Animals respond to signals and cues in their environment. The difference between a signal (e.g. a pheromone) and a cue (e.g. a waste product) is that the information content of a signal is subject to natural selection, whereas that of a cue is not. The model free-living nematode Caenorhabditis elegans forms an alternative developmental morph (the dauer larva) in response to a so-called 'dauer pheromone', produced by all worms. We suggest that the production of 'dauer pheromone' has no fitness advantage for an individual worm and therefore we propose that 'dauer pheromone' is not a signal, but a cue. Thus, it should not be called a pheromone.