Chen P-J et al. (2000) Dev Biol "A novel member of the tob family of proteins controls sexual fate in Caenorhabditis elegans germ cells."

Ellis RE, Kimble JE, Singal A, Chen P-J

[Dev Biol, 2000]

Although many cell fates differ between males and females, probably the most ancient type of sexual dimorphism is the decision of germ cells to develop as sperm or as oocytes. Genetic analyses of Caenorhabditis elegans suggest that fog-3 might directly control this decision. We used transformation rescue to clone the fog-3 gene and show that it produces a single major transcript of approximately 1150 nucleotides. This transcript is predicted to encode a protein of 263 amino acids. One mutation causes a frame shift at the sixth codon and is thus likely to define the null phenotype of fog-3. Although the carboxyl-terminus of FOG-3 is novel, the amino-terminal domain is similar to that of the Tob, BTG1, and BTG2 proteins from vertebrates, which might suppress proliferation or promote differentiation. This domain is essential for FOG-3 activity, since six of eight missense mutations map to this region. Furthermore, this domain of BTG1 and BTG2 interacts with a transcriptional regulatory complex that has been conserved in all eukaryotes. Thus, one possibility is that FOG-3 controls transcription of genes required for germ cells to initiate spermatogenesis rather than oogenesis. This model implies that FOG-3 is required throughout an animal's life for germ cells to initiate spermatogenesis. We used RNA-mediated interference to demonstrate that fog-3 is indeed required continuously, which is consistent with this model.

Xiong, Lei et al. (2010) C. elegans: Development and Gene Expression, EMBL, Heidelberg, Germany "Involvement of a food sensing signaling, the DAF-2 signaling pathway, in the clearance of germ cell corpses"

Hengartner, Michael, Xiong, Lei

[C. elegans: Development and Gene Expression, EMBL, Heidelberg, Germany, 2010]

During both development and stress response, many C.elegans hemaphrodite germ cells die by apoptosis, which is followed by a rapid engulfment and subsequent phagocytosis of apoptotic cells. Many components required for the clearance of germ cell corpses are known. However, the physiological meaning of germ cell phagocytosis is unknown. One hypothesis is that worms could exploit germ cell corpses for fuel when food is limited. Here we report that a DAF-2/AGE-1/PDK-1-dependent but DAF-16-independent singaling pathway is involved in the regulation of phagocytosis of germ cell corpses. In these food sensing mutants, the clearance of apoptotic germ cells both after DNA damage and during development is much faster. Both daf-2 mutation and daf-2 RNAi feeding reduced the number of germ cell corpses after irradiation or during development. Furthermore, phagocytosis in soma was not affected in daf-2 mutant. Unexpectedly, engulfment mutations could suppress the reduction of germ cell corpses in daf-2 mutant, indicating DAF-2 signaling negatively regulates the degradation of apoptotic germ cells. Further experiments showed that daf-2 signaling inhibits the clearance of germ cell corpses in intestine but not in neuronal cells. We are now in the way to investigate how this faster phagocytosis of germ cell corpses in daf-2 mutants is linked to energy homeostasis. Our findings imply that worms have adapted a mechanism to exploit the germ cell corpses for maintaing energy upon food restriction.

Bhagwati P Gupta et al. (2001) International C. elegans Meeting "Regulation and function of lin-11 in vulval development"

Bhagwati P Gupta, Paul W Sternberg

[International C. elegans Meeting, 2001]

C. elegans vulva is an excellent model system to study the mechanisms of cell fate specification during animal development. Of the six v ulval p recursor c ells (VPCs) - Pn.p (n=3-8), three - P5.p, P6.p and P7.p - are induced by lin-3/let-23 mediated ras -singaling pathway to adopt the 2 o -1 o -2 o fates, respectively. These VPCs then undergo three rounds of cell division to produce 22 progeny that differentiate to form the 7 specific cell types in adult vulva. We are interested in identifying and studying the function of genes that regulate the terminal differentiation process of vulval cells. In the past several years many such genes have been identified including lin-11, lin-17 and lin-18 . While the molecular nature of these genes is known, their biology is poorly understood. We are currently working on the lin-11 gene and its regulation in vulval development. LIN-11 is a founding member of the LIM Homeodomain family of proteins. The loss of lin-11 gene function causes a fully penetrant egg-laying defect (Egl). Pertaining to this, two defects at cellular level have been reported - an abnormal 2 o vulval lineage and a failure of uterine development, namely utse formation. Our work on the lin-11 gene shows that it is required at multiple times during vulval development and functions in both 1 o as well as 2 o cell lineages. We have molecularly characterized its regulatory region and find distinct cis -elements for controlling the gene expression in the vulval cells and uterine pi cells. We further show that both elements are necessary to rescue the lin-11 Egl defect; thus lin-11 is required in both vulva and uterus for the development of a functional egg-laying system. In an attempt to identify the genes that regulate lin-11 , we have done epistasis experiments with a set of known vulval genes and find that lin-17 functions upstream of lin-11 . In addition, we have also carried out a genetic screen using lin-11::gfp transgenic strain and have identified three class of mutants that enhance the vulval gfp expression. We are currently working on these loci to get a better understanding of their role in lin-11 regulation.

Mondoux M A et al. (2010) Aging, Metabolism, Stress, Pathogenesis, and Small RNAs, Madison, WI "O-GlcNAc Cycling and Insulin Signaling Respond to Nutrient Stress in C. elegans"

Mondoux M A, Love D C, Ghosh S, Hanover J A, Krause M W

[Aging, Metabolism, Stress, Pathogenesis, and Small RNAs, Madison, WI, 2010]

Energy homeostasis occupies a central position in biology, as it regulates gene expression, signal transduction, cellular survival, fertility, and lifespan. However, the molecular and genetic responses to excess nutrients are poorly understood. Using C. elegans as a genetic model to study the pathways that respond to nutrient stress, we have identified roles for O-GlcNAc cycling and insulin signaling in the glucose stress response. O-GlcNAc (O-linked-N-acetyl glucosamine) is a post-translational modification catalyzed by the O-GlcNAc transferase OGT-1 and the O-GlcNAcase OGA-1. Glucose levels influence O-GlcNAc modification levels, suggesting that the pathway acts as a nutrient sensor. Over 500 nuclear and cytoplasmic proteins are O-GlcNAc modified, including components of the insulin-signaling pathway. In addition, OGA-1 is a human type II diabetes susceptibility locus. Although these enzymes are essential in mammals and highly conserved in C. elegans, knockouts of oga-1 and ogt-1 are viable in the worm. Our previous work demonstrated that O-GlcNAc cycling regulates insulin signaling in the insulin-like receptor mutant daf-2. Null mutations in ogt-1 selectively enhance daf-2 insulin signaling, leading to decreased dauer formation and lifespan with no effect on fertility. Conversely, oga-1 mutations extend daf-2 lifespan, and this effect is partially dependent on the DAF-16 transcription factor. We tested whether the O-GlcNAc cycling or insulin signaling pathways were involved in the genetic response to nutrient stress. We find that ogt-1 mutants show decreased fertility on high glucose. We also found that excess glucose is an enhancer of insulin signaling, suppressing daf-2 dauer formation. Furthermore, combining glucose stress with decreased insulin signaling in a daf-2 ogt-1 double mutant results in increased carbohydrate storage, decreased fertility, and a partial restoration of dauer formation. These data suggest that O-GlcNAc cycling and its regulation of the insulin-singaling pathway are necessary for the maintenance of energy homeostasis in response to glucose stress. We are currently screening a C. elegans RNAi library to identify additional factors that, like ogt-1, suppress insulin signaling in the presence of glucose stress. This screen will identify additional pathways that respond to nutrient stress and will provide insight into how cells respond to nutrient stress when insulin signaling is compromised.

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.