scholarly journals egl-4 Acts Through a Transforming Growth Factor-β/SMAD Pathway in Caenorhabditis elegans to Regulate Multiple Neuronal Circuits in Response to Sensory Cues

Genetics ◽  
2000 ◽  
Vol 156 (1) ◽  
pp. 123-141 ◽  
Author(s):  
Susan A Daniels ◽  
Michael Ailion ◽  
James H Thomas ◽  
Piali Sengupta
Keyword(s):  
Caenorhabditis Elegans ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Egg Laying ◽  
Sensory Cues ◽  
C Elegans ◽  
Epistasis Analysis ◽  
Dauer Larva ◽  
Dauer Formation ◽  
Chemosensory Behavior

Abstract Sensory cues regulate several aspects of behavior and development in Caenorhabditis elegans, including entry into and exit from an alternative developmental stage called the dauer larva. Three parallel pathways, including a TGF-β-like pathway, regulate dauer formation. The mechanisms by which the activities of these pathways are regulated by sensory signals are largely unknown. The gene egl-4 was initially identified based on its egg-laying defects. We show here that egl-4 has many pleiotropies, including defects in chemosensory behavior, body size, synaptic transmission, and dauer formation. Our results are consistent with a role for egl-4 in relaying sensory cues to multiple behavioral and developmental circuits in C. elegans. By epistasis analysis, we also place egl-4 in the TGF-β-like branch and show that a SMAD gene functions downstream of egl-4 in multiple egl-4-regulated pathways, including chemosensation.

scholarly journals The evolutionarily conserved deubiquitinase UBH1/UCH-L1 augments DAF7/TGF-β signaling, inhibits dauer larva formation, and enhances lung tumorigenesis

2020 ◽  
Vol 295 (27) ◽  
pp. 9105-9120 ◽  
Author(s):  
Asami Nagata ◽  
Fumiko Itoh ◽  
Ayaka Sasho ◽  
Kaho Sugita ◽  
Riko Suzuki ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Transforming Growth Factor ◽  
A549 Cells ◽  
Transforming Growth Factor Β ◽  
Human Homolog ◽  
Loss Of Function ◽  
Lung Tumorigenesis ◽  
Smad Signaling ◽  
C Elegans ◽  
Dauer Larva

Modification of the transforming growth factor β (TGF-β) signaling components by (de)ubiquitination is emerging as a key regulatory mechanism that controls cell signaling responses in health and disease. Here, we show that the deubiquitinating enzyme UBH-1 in Caenorhabditis elegans and its human homolog, ubiquitin C-terminal hydrolase-L1 (UCH-L1), stimulate DAF-7/TGF-β signaling, suggesting that this mode of regulation of TGF-β signaling is conserved across animal species. The dauer larva–constitutive C. elegans phenotype caused by defective DAF-7/TGF-β signaling was enhanced and suppressed, respectively, by ubh-1 deletion and overexpression in the loss-of-function genetic backgrounds of daf7, daf-1/TGF-βRI, and daf4/R-SMAD, but not of daf-8/R-SMAD. This suggested that UBH-1 may stimulate DAF-7/TGF-β signaling via DAF-8/R-SMAD. Therefore, we investigated the effect of UCH-L1 on TGF-β signaling via its intracellular effectors, i.e. SMAD2 and SMAD3, in mammalian cells. Overexpression of UCH-L1, but not of UCH-L3 (the other human homolog of UBH1) or of the catalytic mutant UCH-L1C90A, enhanced TGF-β/SMAD-induced transcriptional activity, indicating that the deubiquitination activity of UCH-L1 is indispensable for enhancing TGF-β/SMAD signaling. We also found that UCH-L1 interacts, deubiquitinates, and stabilizes SMAD2 and SMAD3. Under hypoxia, UCH-L1 expression increased and TGF-β/SMAD signaling was potentiated in the A549 human lung adenocarcinoma cell line. Notably, UCH-L1–deficient A549 cells were impaired in tumorigenesis, and, unlike WT UCH-L1, a UCH-L1 variant lacking deubiquitinating activity was unable to restore tumorigenesis in these cells. These results indicate that UCH-L1 activity supports DAF-7/TGF-β signaling and suggest that UCH-L1's deubiquitination activity is a potential therapeutic target for managing lung cancer.

scholarly journals Effect of a Neuropeptide Gene on Behavioral States in Caenorhabditis elegans Egg-Laying

Genetics ◽  
2000 ◽  
Vol 154 (3) ◽  
pp. 1181-1192 ◽  
Author(s):  
Laura E Waggoner ◽  
Laura Anne Hardaker ◽  
Steven Golik ◽  
William R Schafer
Keyword(s):  
Caenorhabditis Elegans ◽  
Active Phase ◽  
Egg Laying ◽  
Sensory Cues ◽  
Nematode Caenorhabditis Elegans ◽  
Inactive State ◽  
Recessive Mutations ◽  
Inactive Phase ◽  
Behavioral States ◽  
Stimulation Of

Abstract Egg-laying behavior in the nematode Caenorhabditis elegans involves fluctuation between alternative behavioral states: an inactive state, during which eggs are retained in the uterus, and an active state, during which eggs are laid in bursts. We have found that the flp-1 gene, which encodes a group of structurally related neuropeptides, functions specifically to promote the switch from the inactive to the active egg-laying state. Recessive mutations in flp-1 caused a significant increase in the duration of the inactive phase, yet egg-laying within the active phase was normal. This pattern resembled that previously observed in mutants defective in the biosynthesis of serotonin, a neuromodulator implicated in induction of the active phase. Although flp-1 mutants were sensitive to stimulation of egg-laying by serotonin, the magnitude of their serotonin response was abnormally low. Thus, the flp-1-encoded peptides and serotonin function most likely function in concert to facilitate the onset of the active egg-laying phase. Interestingly, we observed that flp-1 is necessary for animals to down-regulate their rate of egg-laying in the absence of food. Because flp-1 is known to be expressed in interneurons that are postsynaptic to a variety of chemosensory cells, the FLP-1 peptides may function to regulate the activity of the egg-laying circuitry in response to sensory cues.

scholarly journals Screening for Presenilin Inhibitors Using the Free-Living Nematode, Caenorhabditis elegans

2004 ◽  
Vol 9 (2) ◽  
pp. 147-152 ◽  
Author(s):  
Brenda R. Ellerbrock ◽  
Eileen M. Coscarelli ◽  
Mark E. Gurney ◽  
Timothy G. Geary
Keyword(s):  
Caenorhabditis Elegans ◽  
High Throughput Screening ◽  
Screening Method ◽  
Genetic System ◽  
Body Cavity ◽  
Egg Laying ◽  
The Body ◽  
Loss Of Function ◽  
C Elegans ◽  
Automated Method

Caenorhabditis elegans contains 3 homologs of presenilin genes that are associated with Alzheimer s disease. Loss-of-function mutations in C. elegans genes cause a defect in egg laying. In humans, loss of presenilin-1 (PS1) function reduces amyloid-beta peptide processing from the amyloid protein precursor. Worms were screened for compounds that block egg laying, phenocopying presenilin loss of function. To accommodate even relatively high throughput screening, a semi-automated method to quantify egg laying was devised by measuring the chitinase released into the culture medium. Chitinase is released by hatching eggs, but little is shed into the medium from the body cavity of a hermaphrodite with an egg laying deficient ( egl) phenotype. Assay validation involved measuring chitinase release from wild-type C. elegans (N2 strain), sel-12 presenilin loss-of-function mutants, and 2 strains of C. elegans with mutations in the egl-36K+ channel gene. Failure to find specific presenilin inhibitors in this collection likely reflects the small number of compounds tested, rather than a flaw in screening strategy. Absent defined biochemical pathways for presenilin, this screening method, which takes advantage of the genetic system available in C. elegans and its historical use for anthelminthic screening, permits an entry into mechanism-based discovery of drugs for Alzheimer s disease. ( Journal of Biomolecular Screening 2004:147-152)

A normally attractive cell interaction is repulsive in two C. elegans mesodermal cell migration mutants

Development ◽  
1991 ◽  
Vol 113 (3) ◽  
pp. 797-803 ◽  
Author(s):  
M.J. Stern ◽  
H.R. Horvitz
Keyword(s):  
Cell Migration ◽  
Caenorhabditis Elegans ◽  
Premature Termination ◽  
Cell Interaction ◽  
Egg Laying ◽  
Wild Type ◽  
Mesodermal Cell ◽  
C Elegans ◽  
Somatic Gonad ◽  
Sex Myoblasts

In wild-type Caenorhabditis elegans hermaphrodites, two bilaterally symmetric sex myoblasts (SMs) migrate anteriorly to flank the precise center of the gonad, where they divide to generate the muscles required for egg laying (J. E. Sulston and H. R. Horvitz (1977) Devl Biol. 56, 110–156). Although this migration is largely independent of the gonad, a signal from the gonad attracts the SMs to their precise final positions (J. H. Thomas, M. J. Stern and H. R. Horvitz (1990) Cell 62, 1041–1052). Here we show that mutations in either of two genes, egl-15 and egl-17, cause the premature termination of the migrations of the SMs. This incomplete migration is caused by the repulsion of the SMs by the same cells in the somatic gonad that are the source of the attractive signal in wild-type animals.

scholarly journals Identification of tgh-2, a Filarial Nematode Homolog of Caenorhabditis elegans daf-7 and Human Transforming Growth Factor β, Expressed in Microfilarial and Adult Stages of Brugia malayi

2000 ◽  
Vol 68 (11) ◽  
pp. 6402-6410 ◽  
Author(s):  
Natalia Gomez-Escobar ◽  
William F. Gregory ◽  
Rick M. Maizels
Keyword(s):  
Caenorhabditis Elegans ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Expressed Sequence Tag ◽  
Signal Sequence ◽  
Brugia Malayi ◽  
Transforming Growth Factor Β ◽  
Lung Epithelial Cells ◽  
Filarial Nematode ◽  
Mature Adult

ABSTRACT A novel member of the transforming growth factor β (TGF-β) family has been identified in the filarial nematode parasiteBrugia malayi by searching the recently developed Expressed Sequence Tag (EST) database produced by the Filarial Genome Project. Designated tgh-2, this new gene shows most similarity to a key product regulating dauer larva formation in Caenorhabditis elegans (DAF-7) and to the human down-modulatory cytokine TGF-β. Homology to DAF-7 extends throughout the length of the 349-amino-acid (aa) protein, which is divided into an N-terminal 237 aa, including a putative signal sequence, a 4-aa basic cleavage site, and a 108-aa C-terminal active domain. Similarity to human TGF-β is restricted to the C-terminal domain, over which there is a 32% identity between TGH-2 and TGF-β1, including every cysteine residue. Expression of tgh-2 mRNA has been measured over the filarial life cycle. It is maximal in the microfilarial stage, with lower levels of activity around the time of molting within the mammal, but continues to be expressed by mature adult male and female parasites. Expression in both the microfilaria, which is in a state of arrested development, and the adult, which is terminally differentiated, indicates that tgh-2 may play a role other than purely developmental. This is consistent with our observation that TGH-2 is secreted by adult worms in vitro. Recombinant TGH-2 expressed in baculovirus shows a low level of binding to TGF-β-receptor bearing mink lung epithelial cells (MELCs), which is partially inhibited (16 to 39%) with human TGF-β, and activates plasminogen activator inhibitor-1 transcription in MELCs, a marker for TGF-β-mediated transduction. Further tests will be required to establish whether the major role of B. malayi TGH-2 (Bm-TGH-2) is to modulate the host immune response via the TGF-β pathway.

scholarly journals A functional study of all 40 Caenorhabditis elegans insulin-like peptides

2018 ◽  
Vol 293 (43) ◽  
pp. 16912-16922 ◽  
Author(s):  
Shanqing Zheng ◽  
Hilton Chiu ◽  
Jeffrey Boudreau ◽  
Tony Papanicolaou ◽  
William Bendena ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Life Span ◽  
Peptide Ligands ◽  
Peptide Sequence ◽  
Functional Study ◽  
C Elegans ◽  
Multiple Phenotypes ◽  
Dauer Formation ◽  
Pleiotropic Function

The human genome encodes 10 insulin-like genes, whereas the Caenorhabditis elegans genome remarkably encodes 40 insulin-like genes. Knockout strategies to determine the roles of all the insulin/insulin-like peptide ligands (INS) in C. elegans has been challenging due to functional redundancy. Here, we individually overexpressed each of the 40 ins genes pan-neuronally, and monitored multiple phenotypes including: L1 arrest life span, neuroblast divisions under L1 arrest, dauer formation, and fat accumulation, as readouts to characterize the functions of each INS in vivo. Of the 40 INS peptides, we found functions for 35 INS peptides and functionally categorized each as agonists, antagonists, or of pleiotropic function. In particular, we found that 9 of 16 agonistic INS peptides shortened L1 arrest life span and promoted neuroblast divisions during L1 arrest. Our study revealed that a subset of β-class INS peptides that contain a distinct F peptide sequence are agonists. Our work is the first to categorize the structures of INS peptides and relate these structures to the functions of all 40 INS peptides in vivo. Our findings will promote the study of insulin function on development, metabolism, and aging-related diseases.

scholarly journals NEUROPHYSIOLOGICAL AND BEHAVIOURAL PERTURBATIONS IN Caenorhabditis elegans EXPOSED TO ORGANOPHOSPHATE PESTICIDES

2021 ◽  
Vol 9 (3) ◽  
pp. 343-352
Author(s):  
Rajul Jain ◽  
◽  
Priyanka Gautam ◽  
Keyword(s):  
Caenorhabditis Elegans ◽  
Fluorescent Protein ◽  
Developmental Toxicity ◽  
Yellow Fluorescent Protein ◽  
Model Organism ◽  
Egg Laying ◽  
High Exposure ◽  
C Elegans ◽  
Significant Difference ◽  
Green Fluorescent

The ubiquitous use of pesticides all over the world leads to adverse effects on both targets as well as non-target species. The extensive and uncontrolled use of organophosphates (OPs), a large group of pesticidal compounds in agricultural and household products are resulting in high exposure to humans. This research has been carried out to study the adverse effect of OPs i.e., chlorpyrifos, trichlorfon, and disulfoton on model organism Caenorhabditis elegans to evaluate their behavioural as well as developmental toxicity at different time intervals i.e., 4, 24, 48, and 72 hours (hrs) of exposure. A significant difference was observed in all the behavioural endpoints like locomotion, egg-laying, offspring count, and learning along with developmental parameters like mortality, paralysis, and growth rendering from moderate to high toxic effects. Based on the above screening, trichlorfon resulted in glutamatergic and cholinergic neurodegeneration along with elevated autofluorescence. Loss in Yellow fluorescent Protein (YFP) and Green Fluorescent Protein (GFP) was recorded by 57.96% and 30.52% using transgenic strains OH11124 (otIs388 [eat-4(fosmid)::SL2::YFP::H2B + (pBX)pha-1(+)] III) and OH13083 (otIs576 [unc-17(fosmid)::GFP + lin-44::YFP]). These results have shown the biological potency of toxicants in C. elegans and pave the way forward to provide insight into various neurogenerative diseases in humans.

scholarly journals Genetic analysis of chemosensory control of dauer formation in Caenorhabditis elegans.

Genetics ◽  
1992 ◽  
Vol 130 (1) ◽  
pp. 105-123 ◽  
Author(s):  
J J Vowels ◽  
J H Thomas
Keyword(s):  
Caenorhabditis Elegans ◽  
Genetic Analysis ◽  
Single Step ◽  
Genetic Interactions ◽  
The Other ◽  
Environmental Cues ◽  
Dauer Larva ◽  
Chemosensory Transduction ◽  
Dauer Formation ◽  
Dauer Larvae

Abstract Dauer larva formation in Caenorhabditis elegans is controlled by chemosensory cells that respond to environmental cues. Genetic interactions among mutations in 23 genes that affect dauer larva formation were investigated. Mutations in seven genes that cause constitutive dauer formation, and mutations in 16 genes that either block dauer formation or result in the formation of abnormal dauers, were analyzed. Double mutants between dauer-constitutive and dauer-defective mutations were constructed and characterized for their capacity to form dauer larvae. Many of the genes could be interpreted to lie in a simple linear epistasis pathway. Three genes, daf-16, daf-18 and daf-20, may affect downstream steps in a branched part of the pathway. Three other genes, daf-2, daf-3 and daf-5, displayed partial or complex epistasis interactions that were difficult to interpret as part of a simple linear pathway. Dauer-defective mutations in nine genes cause structurally defective chemosensory cilia, thereby blocking chemosensation. Mutations in all nine of these genes appear to fall at a single step in the epistasis pathway. Dauer-constitutive mutations in one gene, daf-11, were strongly suppressed for dauer formation by mutations in the nine cilium-structure genes. Mutations in the other six dauer-constitutive genes caused dauer formation despite the absence of functional chemosensory endings. These results suggest that daf-11 is directly involved in chemosensory transduction essential for dauer formation, while the other Daf-c genes play roles downstream of the chemosensory step.

scholarly journals Intergenerational Pathogen-Induced Diapause in Caenorhabditis elegans Is Modulated by mir-243

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Carolaing Gabaldón ◽  
Marcela Legüe ◽  
M. Fernanda Palominos ◽  
Lidia Verdugo ◽  
Florence Gutzwiller ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Noncoding Rna ◽  
Pathogenic Bacteria ◽  
Developmental Change ◽  
Differential Expression Analysis ◽  
Phenotypic Analysis ◽  
Content Type ◽  
C Elegans ◽  
Two Generations ◽  
Dauer Formation

ABSTRACT The interaction and communication between bacteria and their hosts modulate many aspects of animal physiology and behavior. Dauer entry as a response to chronic exposure to pathogenic bacteria in Caenorhabditis elegans is an example of a dramatic survival response. This response is dependent on the RNA interference (RNAi) machinery, suggesting the involvement of small RNAs (sRNAs) as effectors. Interestingly, dauer formation occurs after two generations of interaction with two unrelated moderately pathogenic bacteria. Therefore, we sought to discover the identity of C. elegans RNAs involved in pathogen-induced diapause. Using transcriptomics and differential expression analysis of coding and long and small noncoding RNAs, we found that mir-243-3p (the mature form of mir-243) is the only transcript continuously upregulated in animals exposed to both Pseudomonas aeruginosa and Salmonella enterica for two generations. Phenotypic analysis of mutants showed that mir-243 is required for dauer formation under pathogenesis but not under starvation. Moreover, DAF-16, a master regulator of defensive responses in the animal and required for dauer formation was found to be necessary for mir-243 expression. This work highlights the role of a small noncoding RNA in the intergenerational defensive response against pathogenic bacteria and interkingdom communication. IMPORTANCE Persistent infection of the bacterivore nematode C. elegans with bacteria such as P. aeruginosa and S. enterica makes the worm diapause or hibernate. By doing this, the worm closes its mouth, avoiding infection. This response takes two generations to be implemented. In this work, we looked for genes expressed upon infection that could mediate the worm diapause triggered by pathogens. We identify mir-243-3p as the only transcript commonly upregulated when animals feed on P. aeruginosa and S. enterica for two consecutive generations. Moreover, we demonstrate that mir-243-3p is required for pathogen-induced dauer formation, a new function that has not been previously described for this microRNA (miRNA). We also find that the transcriptional activators DAF-16, PQM-1, and CRH-2 are necessary for the expression of mir-243 under pathogenesis. Here we establish a relationship between a small RNA and a developmental change that ensures the survival of a percentage of the progeny.

EGL-17(FGF) expression coordinates the attraction of the migrating sex myoblasts with vulval induction in C. elegans

Development ◽  
1998 ◽  
Vol 125 (6) ◽  
pp. 1083-1093 ◽  
Author(s):  
R.D. Burdine ◽  
C.S. Branda ◽  
M.J. Stern
Keyword(s):  
Caenorhabditis Elegans ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Egg Laying ◽  
Fibroblast Growth ◽  
Fgf Receptor ◽  
Precise Positioning ◽  
C Elegans ◽  
Guidance Cue ◽  
Sex Myoblasts

During the development of the egg-laying system in Caenorhabditis elegans hermaphrodites, central gonadal cells organize the alignment of the vulva with the sex myoblasts, the progenitors of the egg-laying muscles. A fibroblast growth factor [EGL-17(FGF)] and an FGF receptor [EGL-15(FGFR)] are involved in the gonadal signals that guide the migrations of the sex myoblasts. Here we show that EGL-17(FGF) can act as an instructive guidance cue to direct the sex myoblasts to their final destinations. We find that egl-17 reporter constructs are expressed in the primary vulval cell and that EGL-17(FGF) expression in this cell correlates with the precise positioning of the sex myoblasts. We postulate that EGL-17(FGF) helps to coordinate the development of a functional egg-laying system, linking vulval induction with proper sex myoblast migration.

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