Emmons, S et al. (2015) International Worm Meeting "Whole-animal C. elegans connectomes."

Yakovlev, M, Jarrell, T, Wang, Y, Nguyen, K, Cook, S, Emmons, S, Hall, D

[International Worm Meeting, 2015]

We have assembled for the first time complete wiring diagrams of the entire nervous systems of C. elegans adults of both sexes. For the hermaphrodite, we reanalyzed the electron micrographs that served as the basis for the 1986 publication "The Mind of a Worm" (White et al, 1986). For the male, we combined the posterior connectivity we published previously (Jarrell et al, 2012), obtained by analyzing Cambridge electron micrographs (Sulston et al, 1970), with data from our own series through a male head. For the pharynx we reanalyzed the micrographs analyzed previously by Donna Albertson (Albertson and Thomson, 1976). For some neurons, we added data from new electron micrographs of legacy grids. Notably, we added connectivity of SAB motorneurons to body wall muscles in the head (muscles 1-7); these neurons contribute 37% of the total input to these muscles. Finally, significant gaps still remained: to our knowledge, a region posterior of the vulva (posterior of the N2U series, anterior of the male N2Y series) has never been examined by electron microscopy. To fill in these areas, we added connections to complete the chains of motor neurons and muscles by assuming a regular structure. Connectivity matrices, neuron maps, and synapse lists are available on our website: WormWiring.org. Analysis of the complete, quantitative datasets by graph layout algorithms yields biologically meaningful displays. When an algorithm is applied that utilizes the "spring-electric" approach, in which nodes repel each other uniformly and attract according to the strength of their connectivity (Allegro Layout, allegroviva.com), neurons of similar or related function are grouped together. At the next higher level, clear modules are separated. When the arrangement is graphically illustrated using the display tools of Cytoscape, the functional pathways and hierarchical arrangement of the entire worm neuromuscular system are revealed-the layout closely matches the worm's anatomy. The overall arrangement is the same in both sexes, with the addition in the hermaphrodite of the vulva muscles and circuits and to the male "tail" of the enormous copulatory circuits. Along with the sensory pathways for head contact and for odorants and chemicals, pathways leading from pheromone sensing neurons reveal a sexual circuit in the head, elements of which (AVF, PVQ, and RIM interneurons) are shared by both sexes, along with, in the hermaphrodite, the HSN neurons, and in the male, the CEM sensory neurons and the EF and MCM interneurons (for the new MCM interneurons, see the Abstract by Sammut et al).

Emmons S W et al. (2010) Neuronal Development, Synaptic Function and Behavior, Madison, WI "Neural Circuits for Mating in the C. elegans Male Posterior Nervous System"

Jarrell T, Emmons S W, Hall D H, Wang Y, Bloniarz A, Xu M

[Neuronal Development, Synaptic Function and Behavior, Madison, WI, 2010]

The neurons in the C. elegans male tail form a synaptic network comparable in size to that found in the anterior nerve ring. The complexity of the structure makes reverse engineering of its function a challenge. Neural circuits situated mostly in the pre-anal ganglion receive sensory inputs from over 56 sensory neurons present in 25 different sensilla. In our reconstruction of a single adult animal, about half of the synaptic input to end organs comes directly from sensory neurons. The remainder is channeled in one or two steps through interneurons and neurons that act primarily as motor neurons. By tracing up the network from specific muscle groups or the gonad, and integrating information from experimental analysis of sensory neurons, it is possible to suggest neural pathways for specific sub-behaviors in copulation. The gonad is stimulated by post-cloacal sensilla neurons, spicule neurons, and a subset of the male-specific CP interneurons (CP4-6), presumably for ejaculation. This same set of neurons have output onto body wall muscles and diagonal muscles, suggesting muscle contraction accompanies ejaculation. Spicule Prodding appears to be triggered by direct innervation of oblique and gubernacular muscles by post-cloacal sensilla neurons. The Response step appears to involve the male-specific interneuron PVY. The Turn step may involve male-specific interneurons PVX and CP7-9 along with the motor neuron PDB, one of several examples of a sexually-dimorphic shared neuron with little synaptic activity in the hermaphrodite but extensive involvement in the male. Stopping at the vulva and ejaculation appear to involve male-specific interneuron PVZ, while the shared GABAergic interneuron DVB might be involved in terminating copulation. In a first attempt at reverse engineering, laser ablation of the large interneuron PVX resulted in no discernable effect on male behavior, illustrating the robustness of these circuits. The spectrum of postsynaptic partners in polyadic synapses (58% of chemical synapses) suggests a model in which positive feedback forces the network into one of a small number of discrete stable modes of activity, each with output associated with one of the copulatory sub-behaviors.

Roy PJ et al. (2000) Development "mab-20 encodes Semaphorin-2a and is required to prevent ectopic cell contacts during epidermal morphogenesis in Caenorhabditis elegans."

Culotti JG, Zheng H, Roy PJ, Warren CE

[Development, 2000]

The Semaphorins are a family of secreted and transmembrane proteins known to elicit growth cone repulsion and collapse. We made and characterized a putative null mutant of the C. elegans gene semaphorin-2a (Ce-sema-2a). This mutant failed to complement mutants of mab-20 (Baird, S. E., Fitch, D. H., Kassem, I. A. A. and Emmons, S. W. (1991) Development 113, 515-526). In addition to low-frequency axon guidance errors, mab-20 mutants have unexpected defects in epidermal morphogenesis. Errant epidermal cell migrations affect epidermal enclosure of the embryo, body shape and sensory rays of the male tail. These phenotypic traits are explained by the formation of inappropriate contacts between cells of similar type and suggest that Ce-Sema-2a may normally prevent formation or stabilization of ectopic adhesive contacts between these cells.

Zhao C et al. (1993) Worm Breeder's Gazette "Cloning of the lin-32 Gene"

Emmons SW, Zhao C

[Worm Breeder's Gazette, 1993]

Cloning of the lin-32 gene Connie Zhao and Scott W. Emmons, Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461

Greenwald IS et al. (1983) Worm Breeder's Gazette "Tc1 polymorphisms on the right arm of LGIII."

Hodgkin JA, Greenwald IS

[Worm Breeder's Gazette, 1983]

As starting points for the molecular cloning of lin-12 III and tra-1 III, we have identified several Tc1 polymorphisms linked to these genes. Genomic DNA was prepared from appropriate Bristol/Bergerac hybrid strains, cut with EcoRI, and probed with Tc1 (kindly provided by Scott Emmons). Our data are summarized in the maps below, which give the approximate map locations and EcoRI fragment sizes of the Bergerac-specific Tc1's. [See Figure 1]

Nagai K et al. (2003) Bioorg Med Chem Lett "Synthesis and biological activities of novel 4"-alkylidene avermectin derivatives."

Harder A, Omura S, Nagai K, Sunazuka T, Turberg A, Shiomi K

[Bioorg Med Chem Lett, 2003]

Horner-Emmons reaction of 4"-dehydro-5-O-TBDMS-avermectin B-1a with a variety of phosphorus ylides using LHMDS gave novel 4"-alkylidene avermectin derivatives in high yields. Further modifications led to derivatives bearing diverse functional groups. The new avermectin derivatives showed potent growth inhibitory activity against Artemia salina and Caenorhabditis elegans.

Vinci CR et al. (2007) J Biol Chem "Recognition of age-damaged (R,S)-adenosyl-L-methionine by two methyltransferases in the yeast Saccharomyces cerevisiae."

Vinci CR, Clarke SG

[J Biol Chem, 2007]

The biological methyl donor, S adenosylmethionine (AdoMet), can exist in two diastereoisomeric states with respect to its sulfonium ion. The "S" configuration, (S,S)AdoMet, is the only form that is produced enzymatically as well as the only form used in almost all biological methylation reactions. Under physiological conditions, however, the sulfonium ion can spontaneously racemize to the "R" form, producing (R,S)AdoMet. As of yet, (R,S)AdoMet has no known physiological function and may inhibit cellular reactions. In this study, two enzymes have been found in Saccharomyces cerevisiae that are capable of recognizing (R,S)AdoMet and using it to methylate homocysteine to form methionine. These enzymes are the products of the SAM4 and MHT1 genes, previously identified as homocysteine methyltransferases dependent upon AdoMet and S-methylmethionine respectively. We find here that Sam4 recognizes both (S,S) and (R,S)AdoMet, but its activity is much higher with the R,S form. Mht1 reacts with only the R,S form of AdoMet while no activity is seen with the S,S form. R,S-specific homocysteine methyltransferase activity is also shown here to occur in extracts of Arabidopsis thaliana, Drosophila melanogaster, and Caenorhabditis elegans, but has not been detected in several tissue extracts of Mus musculus. Such activity may function to prevent the accumulation of (R,S)AdoMet in these organisms.

Fanning S et al. (2018) Mol Cell "Lipidomic Analysis of -Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment."

Termine D, Becuwe M, Hofbauer HF, Barrasa MI, Pincus D, Imberdis T, Selkoe D, Freyzon Y, Srinivasan S, Soldner F, Nuber S, Sandoe J, Haque A, Welte MA, Clish CB, Terry-Kantor E, Jaenisch R, Kohlwein SD, Fanning S, Dettmer U, Walther TC, Kim TE, Farese RV, Landgraf D, Baru V, Noble T, Lou Y, Lindquist S, Newby G, Ho GPH, Ramalingam N

[Mol Cell, 2018]

In Parkinson's disease (PD), -synuclein (S) pathologically impacts the brain, a highly lipid-rich organ. We investigated how alterations in S or lipid/fattyacid homeostasis affect each other. Lipidomic profiling of human S-expressing yeast revealed increases in oleic acid (OA, 18:1), diglycerides, and triglycerides. These findings were recapitulated in rodent and human neuronal models of S dyshomeostasis (overexpression; patient-derived triplication or E46K mutation; E46K mice). Preventing lipid droplet formation or augmenting OA increased S yeast toxicity; suppressing the OA-generating enzyme stearoyl-CoA-desaturase (SCD) was protective. Genetic or pharmacological SCD inhibition ameliorated toxicity in S-overexpressing rat neurons. In a C.elegans model, SCD knockout prevented S-induced dopaminergic degeneration. Conversely, we observed detrimental effects of OA on S homeostasis: in human neural cells, excess OA caused S inclusion formation, which was reversed by SCD inhibition. Thus, monounsaturated fatty acid metabolism is pivotal for S-induced neurotoxicity, and inhibiting SCD represents a novel PD therapeutic approach.

Vandecandelaere I et al. (2017) PLoS One "Metabolic activity, urease production, antibiotic resistance and virulence in dual species biofilms of Staphylococcus epidermidis and Staphylococcus aureus."

Coenye T, Van Nieuwerburgh F, Deforce D, Vandecandelaere I

[PLoS One, 2017]

In this paper, the metabolic activity in single and dual species biofilms of Staphylococcus epidermidis and Staphylococcus aureus isolates was investigated. Our results demonstrated that there was less metabolic activity in dual species biofilms compared to S. aureus biofilms. However, this was not observed if S. aureus and S. epidermidis were obtained from the same sample. The largest effect on metabolic activity was observed in biofilms of S. aureus Mu50 and S. epidermidis ET-024. A transcriptomic analysis of these dual species biofilms showed that urease genes and genes encoding proteins involved in metabolism were downregulated in comparison to monospecies biofilms. These results were subsequently confirmed by phenotypic assays. As metabolic activity is related to acid production, the pH in dual species biofilms was slightly higher compared to S. aureus Mu50 biofilms. Our results showed that S. epidermidis ET-024 in dual species biofilms inhibits metabolic activity of S. aureus Mu50, leading to less acid production. As a consequence, less urease activity is required to compensate for low pH. Importantly, this effect was biofilm-specific. Also S. aureus Mu50 genes encoding virulence-associated proteins (Spa, SplF and Dps) were upregulated in dual species biofilms compared to monospecies biofilms and using Caenorhabditis elegans infection assays, we demonstrated that more nematodes survived when co-infected with S. epidermidis ET-024 and S. aureus mutants lacking functional spa, splF or dps genes, compared to nematodes infected with S. epidermidis ET-024 and wild- type S. aureus. Finally, S. epidermidis ET-024 genes encoding resistance to oxacillin, erythromycin and tobramycin were upregulated in dual species biofilms and increased resistance was subsequently confirmed. Our data indicate that both species in dual species biofilms of S. epidermidis and S. aureus influence each other's behavior, but additional studies are required necessary to elucidate the exact mechanism(s) involved.

Kamp F et al. (2010) EMBO J "Inhibition of mitochondrial fusion by -synuclein is rescued by PINK1, Parkin and DJ-1."

Kamp F, Winklhofer KF, Giese A, Lutz AK, Brunner B, Wender N, Hegermann J, Haass C, Eimer S, Bartels T, Beyer K, Exner N, Nuscher B

[EMBO J, 2010]

Aggregation of -synuclein (S) is involved in the pathogenesis of Parkinson's disease (PD) and a variety of related neurodegenerative disorders. The physiological function of S is largely unknown. We demonstrate with in vitro vesicle fusion experiments that S has an inhibitory function on membrane fusion. Upon increased expression in cultured cells and in Caenorhabditis elegans, S binds to mitochondria and leads to mitochondrial fragmentation. In C. elegans age-dependent fragmentation of mitochondria is enhanced and shifted to an earlier time point upon expression of exogenous S. In contrast, siRNA-mediated downregulation of S results in elongated mitochondria in cell culture. S can act independently of mitochondrial fusion and fission proteins in shifting the dynamic morphologic equilibrium of mitochondria towards reduced fusion. Upon cellular fusion, S prevents fusion of differently labelled mitochondrial populations. Thus, S inhibits fusion due to its unique membrane interaction. Finally, mitochondrial fragmentation induced by expression of S is rescued by coexpression of PINK1, parkin or DJ-1 but not the PD-associated mutations PINK1 G309D and parkin 1-79 or by DJ-1 C106A.