Matthews LR et al. (1994) Worm Breeder's Gazette "A Potential C. elegans E2F Homolog: Is it zyg-9?"

Galas S, Matthews LR

[Worm Breeder's Gazette, 1994]

A potential C. elegans E2F homolog: Is it zyg-9? Lisa Matthews and Simon Galas, CRBM, CNRS Montpellier, France

Berger S et al. (2018) Lab Chip "Correction: Long-term C. elegans immobilization enables high resolution developmental studies in vivo."

Aegerter-Wilmsen T, DeMello A, Berger S, Casadevall I Solvas X, Hengartner M, Hajnal A, Lattmann E

[Lab Chip, 2018]

Correction for 'Long-term C. elegans immobilization enables high resolution developmental studies in vivo' by Simon Berger et al., Lab Chip, 2018, 18, 1359-1368.

O'Hern, Patrick et al. (2015) International Worm Meeting "The role of miRNAs at the C. elegans neuromuscular junction: relevance to SMA."

O'Hern, Patrick, Hart, Anne, Simon, Jonah

[International Worm Meeting, 2015]

Spinal Muscular Atrophy (SMA) is a neurological disorder characterized by loss of lower motor neurons. This degeneration is almost exclusively caused by mutations in the SMN1 gene that lead to decreased levels of Survival of Motor Neuron (SMN) protein. smn-1 is the C. elegans ortholog of SMN1, and its' disruption results in motor defects (Briese et al. 2009). It is unknown how decreased SMN protein levels perturbs motor neuron function, however evidence suggests that miRNA misregulation may play a role (Mourelatos et al. 2003). miRNAs are small non-coding RNAs predicted to regulate protein expression of messenger RNAs (mRNAs). The RNA helicase Gemin3 is found in numerous complexes with SMN and also pulls down with miRNAs in cultured mouse motor neurons (Dostie et al. 2003). I hypothesize that Gemin3-associated miRNAs are misregulated in smn-1 loss-of-function animals leading to NMJ defects. Animals lacking SMN or MEL-46, the C. elegans Gemin3 ortholog, are defective in their response to aldicarb, suggesting perturbed NMJ function. Using tissue-specific rescue analysis, I have identified a single miRNA that impacts NMJ function, similar to SMN-1 and MEL-46. I will compile a list of potential mRNA targets for this candidate miRNA utilizing online bioinformatics tools, assigning priority to conserved targets with known synaptic function. For each potential mRNA target, I will verify miRNA regulation and investigate whether target levels are altered in smn-1(lf) and mel-46(lf) animals. Additionally, I have shown that overexpression of MEL-46 improves smn-1(lf) NMJ defects. Given the potential role of Gemin3 in the miRNA pathway, I plan to determine whether this rescue results from restoration of miRNA function. These experiments will delineate miRNA function at the NMJ, advance our knowledge of how loss of SMN protein impacts neuronal function, and inform our understanding of how miRNA misregulation may contribute to neurodegeneration.

Baskoylu, Saba et al. (2015) International Worm Meeting "Decreased SOD-1 function in a precise C. elegans ALS model leads to defective synaptic transmission and stress-induced neurodegeneration."

Yersak, Jill, O'Hern, Patrick, Simon, Jonah, Hart, Anne, Baskoylu, Saba

[International Worm Meeting, 2015]

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of cortical and spinal motor neurons. The second most common cause of familial ALS (fALS) is mutation of Cu/Zn superoxide dismutase 1 (SOD1). These mutations likely confer - as yet unidentified, toxic properties. Consistent with this idea, fALS-SOD1 overexpression recapitulates some end-stage aspects of disease, including dramatic SOD1 aggregation, neuronal dysfunction and death. However, overexpression models may obscure early-stage defects and the potential impacts of diminished fALS-SOD1 activity. Indeed, reminiscent of SOD1 null mice, a precise fALS-SOD1 knock-in mouse model results in peripheral neuropathy (PMID:25468678).To investigate whether SOD1 loss of function contributes to disease and early-stage events, we generated single-copy fALS SOD-1 models in C. elegans. We inserted conserved patient alleles H71Y and G85R into the C. elegans sod-1 gene. fALS sod-1 alleles increased aggregation of human wild-type SOD1-YFP in motor neurons. Both sod-1 loss and fALS sod-1 mutations led to decreased lifespan and hypersensitivity to oxidative stress. Interestingly, both sod-1 null animals and fALS sod-1 animals were hypersensitive to the cholinesterase inhibitor aldicarb. Examination of the fluorescently labeled pre-synaptic proteins in cholinergic motor neurons revealed perturbations in the synaptic transmission machinery of sod-1 loss of function animals. Oxidative stress was sufficient to increase aggregation of human wild-type SOD1-YFP and exacerbated aldicarb hypersensitivity. Intriguingly, stress also induced neurodegeneration of glutamatergic neurons and cholinergic motor neurons in both fALS sod-1 and sod-1 loss of function animals. Our results suggest that exposure to exogenous stress may unmask or aggravate defects observed in fALS sod-1 animals.In summary, we have generated a non-overexpression fALS SOD1 model in C. elegans that may reflect early stage events in ALS pathogenesis. These animals greatly differ from those over-expressing human fALS SOD1 (PMID:19165329). Analysis of sod-1 loss of function and fALS sod-1 animals suggests that loss of SOD-1 function impairs neuromuscular junction activity, impairs stress resistance, and contributes to neurodegeneration.

Davies JB (1993) Ann Trop Med Parasitol "Description of a computer model of forest onchocerciasis transmission and its application to field scenarios of vector control and chemotherapy."

Davies JB

[Ann Trop Med Parasitol, 1993]

This paper describes a computer simulation model for onchocerciasis (SIMON). Using epidemiological and entomological data from a specific hyperendemic village in the forest area of Sierra Leone, the model is used to examine the effect of vector and chemotherapeutic control strategies, both separately and in combination, as well as the risk to an uninfected population caused by immigrant, infected Simulium damnosum and humans. The model suggests that, in this village, the human population of about 420 requires an average annual input of about 200 mature fecund, female Onchocerca volvulus per year to maintain a skin-snip prevalence of just under 70%. SIMON also predicts that 99% effective vector control would lead to eradication of all adult worms in 18 years, and that abandoning control before 14 years could lead to recrudescence. Chemotherapy with ivermectin at six-month intervals reaching 90% of eligible persons (effective 66%) might take 29 years to achieve eradication because of continuing transmission, particularly in the early years, but it would probably be possible to abandon treatments after 18 years because the residual worm population would no longer be self-sustaining. Combined ivermectin and vector control, both at reduced levels, could be as effective as 99% vector control. Immigrant infected flies are likely to pose a greater threat to an uninfected human population than small numbers of infected persons. The model suggests that, at levels of infection undetectable by skin-snip, the parasite could linger in the human population for 30 or more years sustained by sporadic transmission.(ABSTRACT TRUNCATED AT 250 WORDS)

Lars Nilsson et al. (2006) European Worm Meeting "C. elegans NUM-1 Modulates Endocytosis by Targeting the TAT-1 Phospholipid Flippase"

Lars Nilsson, Simon Tuck

[European Worm Meeting, 2006]

Lars Nilsson and Simon Tuck. We have previously reported that C. elegans NUM-1 modulates both endocytosis and the activity of LIN-12, a receptor that mediates a number of cell fate specification events in the worm. In order to understand better how NUM-1 functions, we carried out a yeast 2-hybrid screen for interacting proteins. One clone we isolated encodes TAT-1, a transmembrane P-type ATPase. Work in S. cerevisiae has shown that these proteins function as so-called inward phospholipid flippases to concentrate specific phospholipids to the cytosolic leaflet of biological membranes. They are known to be associated with endosomes and to be required for correct vesicle trafficking. We have found that TAT-1 is expressed in tissues in which NUM-1 functions. Mapping of the regions required for binding revealed that the PTB domain of NUM-1 associates with an NXXF motif at the C-terminus of TAT-1. RNAi experiments show that tat-1 affects membrane trafficking in C. elegans. Our results suggest that NUM-1 functions in the worm by modulating TAT-1 activity.

JJ Yochem (1999) International C. elegans Meeting "Mutations that confer aspects of the molting defects seen with lrp-1 mutations or sterol starvation"

JJ Yochem

[International C. elegans Meeting, 1999]

Mutations that produce larvae that are completely stuck in old cuticle, that have rings of unshed cuticle that constrict regions of the body, or that have attached to the tail a train of old cuticle will be described. Such larvae can be detected with a dissecting microscope, permitting a semi-clonal screen. The search for such mutations was begun because a failure to complete molting is an aspect of the phenotype conferred by loss-of-function mutations in lrp-1 , the product of which resembles mammalian gp330/megalin, a large member of the LDL receptor family of proteins [Yochem et al., Development 126, 597 (1999)]. It is hoped that new mutations will reveal genes whose products are required for the same process as LRP-1. The mutations also have the potential for increasing our understanding of molting, a process that has not been much studied genetically in nematodes. To date, mutations have defined eight candidate genes. Of particular note are mlt-3(sv8) and mlt-7(sv16) , both of which closely resemble the lrp-1 mutant phenotype. Thanks to Simon Tuck, Min Han, and Bob Herman.

Morten K. Larsen et al. (2006) European Worm Meeting "MAA-1, A Novel Acyl-CoA Binding Protein Involved in Endosomal Vesicle Transport in C. elegans"

Morten K. Larsen, Simon Tuck, Jens K. Knudsen, Nils J. Faergeman

[European Worm Meeting, 2006]

Morten K. Larsen1, Simon Tuck1, Nils J. Faergeman2 and Jens K. Knudsen2. The formation of transport vesicles during membrane trafficking requires an intricate interplay between many proteins including those coating the vesicles, adaptor proteins that recruit components of the coat, and small GTPases involved in initiation of vesicle formation. In addition to the protein factors, membrane bilayer lipids are increasingly being recognised as molecules participating actively during vesicle formation. For example, formation of transport carriers is promoted by the hydrolysis of acyl-CoA lipid esters in vitro. The mechanisms by which these lipid esters are directed to the appropriate membranes during vesicle biogenesis is not yet understood. Here we present the first study of MAA-1, a novel member of the acyl-CoA-binding protein family. We show that in C. elegans, MAA-1 is membrane associated and localizes to intracellular membrane organelles in several polarised tissues in C. elegans. MAA-1 binds fatty acyl-CoA in vitro and the ability to form high affinity ligand-protein complexes is necessary for function. Lack of maa-1 reduces the rate of endosomal recycling and enhances phenotypes caused by rme-1, an EH domain protein involved in endosomal recycling. Our results are consistent with a role for acyl-CoA and MAA-1 during endosomal recycling in vivo.

Hom, Sabrina et al. (2009) International Worm Meeting "Identifying genes required for the miR-1 and MEF-2 induced retrograde synaptic signal."

Hom, Sabrina, Kaplan, Joshua, Choi, Seungwon, Thompson-Peer, Katherine, Hu, Zhitao

[International Worm Meeting, 2009]

A fundamental question pertaining to the regulation of synaptic activity concerns how pre- and post-synaptic sites coordinate function. While retrograde signaling has been well-documented in the regulation of synaptic activity, little is known about the molecular mechanisms underlying this phenomenon. We have recently demonstrated that the muscle-specific microRNA miR-1 regulates aspects of both pre- and post-synaptic activity at the NMJ, a process that is thought to involve the generation of a retrograde signal resulting in diminished excitatory presynaptic release (Simon et al., 2008). This signal is dependant on the transcription factor MEF-2, indicating that transcriptional regulation is a key component in the retrograde pathway. We have carried out a microarray analysis of mir-1 mutants that reveals a list of about 100 candidate genes that are up- or down-regulated in the mir-1 background. To distinguish those genes potentially involved in the activation of the MEF-2 dependant retrograde signal, we are currently carrying out a small-scale RNAi screen to identify suppressors of the mir-1 induced signal. In identifying and characterizing components of the retrograde signaling pathway, we hope to clarify the roles of miR-1 and MEF-2 in regulating synaptic activity.

Wang, Xin et al. (2013) International Worm Meeting "Mutations in C9ORF72/F18A1.6 produce developmental and behavioral defects."

Buttner, Edgar, Wang, Xin

[International Worm Meeting, 2013]

Expanded hexanucleotide repeats in the human C9ORF72 gene cause frontotemporal dementia and amyotrophic lateral sclerosis (Boeve et al., 2012; Renton et al., 2011). The normal and abnormal mechanisms of action of this human disease gene are not fully understood. We are characterizing phenotypes associated with mutations in F18A1.6, the C. elegans homolog of C9ORF72. We found that feeding RNAi of F18A1.6 caused developmental delay, while the insertion/deletion allele ok3062 did not. F18A1.6(RNAi) also reduced locomotor behavior in a thrashing assay, compared to empty-vector control. Surprisingly, ok3062 animals displayed increased thrashing, compared to N2. To better understand the cellular basis of the locomotion phenotypes, we are now conducting pharmacological and neuronal GFP reporter assays. We are also generating transgenic animals to test the ability of C9ORF72 to rescue F18A1.6-associated phenotypes and to test the effects of expressing expanded hexanucleotide repeats in C. elegans. References Boeve, K. B. Boylan, N. R. Graff-Radford, M. DeJesus-Hernandez, D. S. Knopman, O. Pedraza, and P. Vemuri (2012). Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 135, 765-783. Renton, E. Majounie, A. Waite, J. Simon-Sanchez, S. Rollinson, J. R. Gibbs, J. C. Schymick, and H. Laaksovirta (2011). A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257-268.