White JG et al. (1980) Worm Breeder's Gazette "observations on the development of the ventral hypodermis."

Thomson JN, Anness M, White JG

[Worm Breeder's Gazette, 1980]

In the course of our studies of the ventral nerve cord we have reconstructed the ventral hypodermis of several animals from electron- micrographs of serial sections. Although only a few developmental stages have been sampled some of the observations may be of general interest. 5 Hours Post-Hatch. At this stage the ventral hypodermis is cellular, the bulk of it being made up of the ventral cord precursor or 'P' cells. These are arranged as 6 pairs of bilaterally symmetrical cells with laterally situated nuclei. Each cell is joined to its symmetrical partner by a desmosome which is situated exactly on the ventral mid-line. The seam or 'V' cells are starting to divide at this time. The anterior regions of these cells send processes which run ventrally and meet at the ventral mid-line, thus separating pairs of P cells. It seems as if these regions start behaving like ventral syncytial hypodermal cells (the ultimate fate of the anterior daughter) before the divisions of the V cells are complete. [See figure 1] 18 Hours Post-Hatch. The seam cells have all completed their divisions and the cytoplasm of the syncytial anterior daughter cells has spread ventrally, undercutting that of the p cells laterally. The P cell nuclei and lateral cytoplasm are migrating into the ventral cord at this stage. The bilateral symmetry is lost at this point as the P cells arrange themselves as a single atero/posterior file. Left may end up either anterior or posterior to right although one configuration is usually favoured. 10 Hours Post-Hatch. The P cells start to divide, budding off an anterior daughter. The posterior part of the cell maintains its desmosome belt attachments to adjacent hypodermal cells throughout cleavage. The anterior part has no desmosomes and becomes a neuroblast when cleavage has completed. Subsequent Development. P1, P2 & P9-11 fuse with the hypodermal syncytium by the L1 moult. P3-P8 divide during mid-L3. If the somatic gonad is not present these cells will fuse with the hypodermal syncytium by the adult stage. In normal development P5-P7 will be induced to proliferate and produce a vulva, most of whose cells are unfused in the adult.

White JG et al. (1978) Nature "Connectivity changes in a class of motoneurone during the development of a nematode."

Anness M, White JG, Albertson DG

[Nature, 1978]

The ventral nerve cord of the nematode Caenorhabditis elegans contains a linear array of motoneurones which innervate the body muscles that mediate locomotion. The adult ventral cord has about three times as many cells as that of the first stage larva. The development events that generate the adult complement of cells occur in a period preceding the first larval moult. During this period we find that a class of pre-existing, juvenile motoneurones changes its pattern of connectivity. Neuromuscular junctions are removed from ventral muscles and are reformed onto dorsal muscles. Similarly the dendritic input to these neurones changes over from the dorsal to the ventral side. The structure and connectivity of ventral cord motoneurones in adult hermaphrodites has been determined by serial section reconstruction of electron micrographs. The salient features of the structure are summarised below:

Wypijewska A et al. (2012) Biochemistry "7-methylguanosine diphosphate (m(7)GDP) is not hydrolyzed but strongly bound by decapping scavenger (DcpS) enzymes and potently inhibits their activity."

Wypijewska A, Darzynkiewicz E, Davis RE, Jemielity J, Bojarska E, Lukaszewicz M, Stepinski J

[Biochemistry, 2012]

Decapping scavenger (DcpS) enzymes catalyze the cleavage of a residual cap structure following 3' 5' mRNA decay. Some previous studies suggested that both m(7)GpppG and m(7)GDP were substrates for DcpS hydrolysis. Herein, we show that mononucleoside diphosphates, m(7)GDP (7-methylguanosine diphosphate) and m(3)(2,2,7)GDP (2,2,7-trimethylguanosine diphosphate), resulting from mRNA decapping by the Dcp1/2 complex in the 5' 3' mRNA decay, are not degraded by recombinant DcpS proteins (human, nematode, and yeast). Furthermore, whereas mononucleoside diphosphates (m(7)GDP and m(3)(2,2,7)GDP) are not hydrolyzed by DcpS, mononucleoside triphosphates (m(7)GTP and m(3)(2,2,7)GTP) are, demonstrating the importance of a triphosphate chain for DcpS hydrolytic activity. m(7)GTP and m(3)(2,2,7)GTP are cleaved at a slower rate than their corresponding dinucleotides (m(7)GpppG and m(3)(2,2,7)GpppG, respectively), indicating an involvement of the second nucleoside for efficient DcpS-mediated digestion. Although DcpS enzymes cannot hydrolyze m(7)GDP, they have a high binding affinity for m(7)GDP and m(7)GDP potently inhibits DcpS hydrolysis of m(7)GpppG, suggesting that m(7)GDP may function as an efficient DcpS inhibitor. Our data have important implications for the regulatory role of m(7)GDP in mRNA metabolic pathways due to its possible interactions with different cap-binding proteins, such as DcpS or eIF4E.

O'Connell EM et al. (2015) J Infect Dis "Targeting Filarial Abl-like Kinases: Orally Available, Food and Drug Administration-Approved Tyrosine Kinase Inhibitors Are Microfilaricidal and Macrofilaricidal."

Nutman TB, O'Connell EM, Bennuru S, Steel C, Dolan MA

[J Infect Dis, 2015]

BACKGROUND: Elimination of onchocerciasis and lymphatic filariasis is targeted for 2020. Given the coincident Loa loa infections in Central Africa and the potential for drug resistance development, the need for new microfilaricides and macrofilaricides has never been greater. With the genomes of L. loa, Onchocerca volvulus, Wuchereria bancrofti, and Brugia malayi available, new drug targets have been identified. METHODS: The effects of the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib on B. malayi adult males, adult females, L3 larvae, and microfilariae were assessed using a wide dose range (0-100 M) in vitro. RESULTS: For microfilariae, median inhibitory concentrations (IC50 values) on day 6 were 6.06 M for imatinib, 3.72 M for dasatinib, and 81.35 M for nilotinib; for L3 larvae, 11.27 M, 13.64 M, and 70.98 M, respectively; for adult males, 41.6 M, 3.87 M, and 68.22 M, respectively; and for adult females, 42.89 M, 9.8 M, and >100 M, respectively. Three-dimensional modeling suggests how these tyrosine kinase inhibitors bind and inhibit filarial protein activity. CONCLUSIONS: Given the safety of imatinib in humans, plans are underway for pilot clinical trials to assess its efficacy in patients with filarial infections.

Albertson DG et al. (1977) Worm Breeder's Gazette "Development of the Phasmid Socket"

Anness M, White JG, Sulston JE, Albertson DG

[Worm Breeder's Gazette, 1977]

The phasmid is a sensilla in the tail analogous to the amphids in the head and probably functions as a chemosensory receptor. Like most sensillae it is apparently attached to the hypodermis by a specialized cell, the socket cell. The phasmid socket cell is derived from the T. seam cell after 3 rounds of division that occur in the first larval stage. The sister of the socket cell differentiates into a cell of unknown function which has been nick-named the 'wing' cell. In the hermaphrodite the lineage of the socket cell is T.Paa, whereas the wing is T.PaP. In the male these allocations are reversed. A male and hermaphrodite were fixed and sectioned in L2 lethargus to try to find out the reason for this reversal. It was found that at this stage (i.e. about 5 hours after the socket and wing had been born) both these cells looked like socket cells, one being concentric to the other, both in the hermaphrodite and in the male. Thus it seems that soon after birth these two cells are equivalent and that in the course of development one gets transformed into a wing cell; either may be chosen to do this depending on the sex of the animal. A further animal was fixed about 5 hours after hatching (i.e. before the T. cell had divided) and reconstructed. It was found that in this case the posterior part of the T. seam cell was functioning as a socket cell. The socket and wing cells are ultimately derived from the posterior daughter of the first division of the T. seam cell so that it seems that this differentiated function is propagated through the lineage.

Albertson DG et al. (1977) Worm Breeder's Gazette "ventral cord motor neuron ablation experiments."

Sulston JE, White JG, Anness M, Albertson DG

[Worm Breeder's Gazette, 1977]

White JG et al. (1976) Worm Breeder's Gazette "studies on the structures of the ventral cords of developmental mutants."

Southgate E, Anness M, Sulston JE, White JG

[Worm Breeder's Gazette, 1976]

We have been studying the ventral cords of two mutants which fail at different stages in the period of post-embryonic development which occurs just prior to the L1 moult. In one mutant, E1348 isolated by J. E. Sulston, the precursors, which would normally give rise to 5 neurones and one hypodermal cell, do not divide while in the second, E1414, isolated by H. R. Horvitz, only the last rounds of division are variably blocked. In both these mutants the structure and organization of the juvenile set of motor neurones is the same as that in the wild-type adults. The 'precursor' cells in H86 generally turn out to be motor neurones, although one case has been seen where one had become a hypodermal cell which had fused with the hypodermal syncytium. The neurone-like cells have many more branches than normal motor neurones and show some of the characteristics of the individual neurones that would normally be produced from these cells, such as the characteristic dendritic spines of the class D motor neurones. In the case of E1414, some of the neuroblasts that would normally give rise to a type A and a B or an AS and a VD motor neurone fail in this terminal division. These cells take on the characteristics of their posterior daughters i.e. a class B and a class VD, both in terms of their morphology and synaptic input. Those neuroblasts that divide normally produce normal looking progeny cells.

Wood WB (1976) Worm Breeder's Gazette "maternal effects among ts zygote-defective (zyg) mutants."

Wood WB

[Worm Breeder's Gazette, 1976]

We have studied maternal effects in 23 zyg ts mutants to estimate the times of expression of genes whose products are required in embryogenesis. We have used the following three tests, called arbitrarily A, B, and C. A test: Heterozygous (m/+) L4's are shifted to 25 C and allowed to self-fertilize. If 100% of their eggs yield larvae (25% of which express the mutant phenotype as adults), then the mutant is scored as maternal (M). If 25% of the F1 eggs fail to hatch, then the mutant is scored as non-maternal (N). An M result indicates that expression of the + allele in the parent allows m/m zygotes to hatch and grow to adulthood. A result of N indicates the opposite: that the + allele must be expressed in the zygote for hatching to occur. Out of 23 zyg mutants tested, 3 were scored N and 20 were scored M in the A test. Therefore, for most of the genes defined by these mutants, expression in the parent is sufficient for zygote survival, even if the gene is not expressed in the zygote. B test: Homozygous (m/m) hermaphrodites reared at 25 C are mated with N2 (+/+) males. If eggs fail to hatch at 25 C, but mated hermaphrodites shifted to 16 C produce cross progeny to give proof of mating, then the mutant is scored M. If cross progeny appear in the 25 C mating, then the mutant is scored N. An M result indicates that expression of the + allele in the zygote is not sufficient to allow m/+ progeny of an m/m hermaphrodite to survive. Conversely an N result indicates either that zygotic expression of the + allele is sufficient for survival, or that a sperm function or factor needed for early embryogenesis can be supplied paternally (see C test below). Out of the 23 zyg mutants tested, 11 were scored M and 12 were scored N. The combined results of A and B tests and their simplest interpretation are as follows. Ten mutants are M,M; the genes defined by these mutants must be expressed in the hermaphrodite parent for the zygote to survive. Ten mutants are M,N; these genes can be expressed either in the parent or in the zygote. Two mutants are N,N; these genes must be expressed in the zygote. One mutant is N,M; this gene must be expressed both in the maternal parent and in the zygote. C test: Homozygous (m/m) hermaphrodites reared at 25 C are mated with heterozygous (m/+) males. If rescue by a +/+ male in the B test depends on the + allele, then only half the cross progeny zygotes of a C test mating (m/+ male x m/m hermaphrodite) should survive. However, if rescue depends on a function or cytoplasmic component from the male sperm, then all the cross progeny zygotes in a C test should survive. Of the 10 M,N mutants, 6 have been C tested; one exhibited paternal rescue independent of the + allele. The A and B tests also were carried out on 16 mutants that arrest before the L3 molt (acc mutants). In the A test on 2 of these mutants, all m/m progeny of m/+ parents grew to adulthood at 25 C. Therefore, parental contributions are sufficient to overcome a progeny mutational block as late as the L2 stage. All 16 acc mutants scored N in the B test.

Ali Khan L et al. (1994) Worm Breeder's Gazette "cej-1 Encodes a Novel Protein With Poly-Threonine Motif"

Siddiqui SS, Fukushige T, Ali Khan L, Tsukita Sh, Tabish M, Itoh M

[Worm Breeder's Gazette, 1994]

cej-1 Encodes a Novel Protein with Poly-Threonine Motif M. L. A. Khanl, M. Tabish, T. Fukushigel1 S. Tsukita2, M. Itoh , Sh. Tsukita , and S. S. Siddiqui. (1): Lab. of Molecular Biology, Dept of Ecological Engg. Toyohashi Univ. Technology, Toyohashi 441, and (2). National Institute for Physiological Sciences, Okazaki 444, Japan.

Lemire BD et al. (2009) Mech Ageing Dev "C. elegans longevity pathways converge to decrease mitochondrial membrane potential."

Behrendt M, Decorby A, Lemire BD, Gaskova D

[Mech Ageing Dev, 2009]

Energy production via oxidative phosphorylation generates a mitochondrial membrane potential (DeltaPsi(m)) across the inner membrane. In this work, we show that a lower DeltaPsi(m) is associated with increased lifespan in Caenorhabditis elegans. The long-lived mutants daf-2(e1370), age-1(hx546), clk-1(qm30), isp-1(qm150) and eat-2(ad465) all have a lower DeltaPsi(m) than wild type animals. The lower DeltaPsi(m) of daf-2(e1370) is daf-16 dependent, indicating that the insulin-like signaling pathway not only regulates lifespan but also mitochondrial energetics. RNA interference (RNAi) against 17 genes shown to extend lifespan also decrease DeltaPsi(m). Furthermore, lifespan can be significantly extended with the uncoupler carbonylcyanide-3-chlorophenylhydrazone (CCCP), which dissipates DeltaPsi(m). We conclude that longevity pathways converge on the mitochondria and lead to a decreased DeltaPsi(m). Our results are consistent with the 'uncoupling to survive' hypothesis, which states that dissipation of the DeltaPsi(m) will extend lifespan.