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Developmental Cell,
2004]
The X chromosome is largely inactivated in spermatogenesis of heterogametic males, and in multiple phyla it encodes few genes specifically expressed in the male germline. Writing in Nature Genetics, Bean et al. report a parallel between male germline X inactivation in nematodes and a fungal gene-silencing mechanism that alters the way we view the evolution of both phenomena.
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Adv Exp Med Biol,
2013]
Germ cells share core attributes and homologous molecular components across animal phyla. Nevertheless, abrupt shifts in reproductive mode often occur that are mediated by the rapid evolution of germ cell properties. Studies of Caenorhabditis nematodes show how the otherwise conserved RNA-binding proteins (RBPs) that regulate germline development and differentiation can undergo surprisingly rapid functional evolution. This occurs even as the narrow biochemical tasks performed by the RBPs remain constant. The biological roles of germline RBPs are thus highly context-dependent, and the inference of archetypal roles from isolated models in different phyla may therefore be premature.
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Curr Top Dev Biol,
2009]
A number of major adaptations in animals have been mediated by alteration of germ cells and their immediate derivatives, the gametes. Here, several such cases are discussed, including examples from echinoderms, vertebrates, insects, and nematodes. A feature of germ cells that make their development (and hence evolution) distinct from the soma is the prominent role played by posttranscriptional controls of mRNA translation in the regulation of proliferation and differentiation. This presents a number of special challenges for investigation of the evolution of germline development. Caenorhabditis nematodes represent a particularly favorable system for addressing these challenges, both because of technical advantages and (most importantly) because of natural variation in mating system that is rooted in alterations of germline sex determination. Recent studies that employ comparative genetic methods in this rapidly maturing system are discussed, and likely areas for future progress are identified.
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Mol Biochem Parasitol
]
Filarial nematodes cause long-term infections in hundreds of millions of people. A significant proportion of those affected develop a number of debilitating health problems but, remarkably, such infections are often unnoticed for many years. It is well known that parasitic worms modulate, yet do not completely inhibit, host immunological pathways, promoting their survival by limiting effective immune mechanisms. Such immunoregulation largely depends on molecules released by the worms, termed excretory-secretory products (ES). One of these products is the molecule ES-62, which is actively secreted by the rodent filarial nematode Acanthocheilonema viteae. ES-62 has been shown to exert anti-inflammatory actions thorough its phosphorylcholine (PC)-containing moiety on a variety of cells of the immune system, affecting intracellular signalling pathways associated with antigen receptor- and TLR-dependent responses. We summarise here how ES-62 modulates key signal transduction elements and how such immunomodulation confers protection to mice subjected to certain experimental models of inflammatory disease. Finally, we discuss recent results showing that it is possible to synthetise small molecule analogues (SMAs) that mimic the anti-inflammatory properties of ES-62, opening an exciting new drug development field in translational medicine.
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Trends Genet,
2012]
Reproduction is directly connected to the suite of developmental and physiological mechanisms that enable it, but how it occurs also has consequences for the genetics, ecology and longer term evolutionary potential of a lineage. In the nematode Caenorhabditis elegans, anatomically female XX worms can self-fertilize their eggs. This ability evolved recently and in multiple Caenorhabditis lineages from male-female ancestors, providing a model for examining both the developmental causes and longer term consequences of a novel, convergently evolved reproductive mode. Here, we review recent work that implicates translation control in the evolution of XX spermatogenesis, with different selfing lineages possessing both reproducible and idiosyncratic features. We also discuss the consequences of selfing, which leads to a rapid loss of variation and relaxation of natural and sexual selection on mating-related traits, and may ultimately put selfing lineages at a higher risk of extinction.
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Immunology,
2005]
Secretion of immunomodulatory molecules is a key strategy employed by pathogens to enable their survival in host organisms. For example, arthropod-transmitted filarial nematodes, which achieve longevity within the infected host by suppressing and modulating the host immune response, produce excretory-secretory (ES) products that have been demonstrated to possess immunomodulatory properties. In this review we discuss the immunomodulatory effects of the phosphorylcholine-containing filarial nematode-secreted glycoprotein ES-62 and describe the intracellular signal transduction pathways it targets to achieve these effects.
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Curr Protein Pept Sci,
2003]
ES-62 is a major secreted glycoprotein of the rodent filarial nematode Acanthocheilonema viteae and homologue of molecules found in filarial nematodes which parasitise humans. The molecule consists of a tetramer of apparently identical monomers of ~62 kDa which we have shown by sedimentation equilibrium analytical ultracentrifugation to strongly associate. ES-62 is one of several filarial nematode proteins to contain the unusual post-translational modification of phosphorylcholine (PC) addition. Specifically, we have found that PC is attached to one of three distinct N-type glycans we have characterised on the molecule. The amino acid sequence of ES-62 shows 37-39% identity with a family of 6 other proteins, some of which have been predicted to be amino- or carboxy-peptidases. We have also found that ES-62 is able to interact with a number of cells of the immune system, specifically B- and T-lymphocytes, macrophages and dendritic cells. Lymphocytes exposed to ES-62 in vitro or in vivo are less able to proliferate in response to ligation via the antigen receptor. Peritoneal macrophages pre-exposed to the molecule are less able to produce the cytokines IL-12, IL-6 and TNF-alpha following subsequent incubation with the classical stimulators IFNgamma and LPS. Dendritic cells allowed to mature in the presence of ES-62 acquire a phenotype, which allows them to induce anti-inflammatory "TH2-type" responses. With respect to immunomodulation, the PC moiety of the parasite molecule appears to be predominantly responsible for the effects on lymphocyte proliferation at least and we have also found that its removal converts the murine IgG antibody response to ES-62 from solely IgG1 to mixed IgG1/IgG2a. ES-62 appears to interact with cells of the immune system in a PC-dependent manner and, at least in part, via a molecule of ~82 kDa. Studies of the interaction in lymphocytes show that it is associated with activation of certain signal transduction molecules including a number of protein tyrosine kinases and mitogen activated protein kinases (MAPkinases). Although such activation is insufficient to induce proliferation, it serves to almost completely desensitise the cells to antigen-receptor ligation-induced activation of the phosphoinositide 3-kinase (PI-3-kinase) and Ras/MAPkinase pathways, events critical for lymphocyte proliferation. Such desensitisation reflects ES-62-primed recruitment of a number of negative regulators of these pathways, such as the phosphatases SHP-1 and Pac-1.
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Trends in Genetics,
1999]
Transgenic technology is currently applied to several animal species of agricultural or medical importance, such as fish, cattle, mosquitos and parasitic worms. However, the repertoire of genetic tools used for molecular analyses of mice and Drosophila is not always applicable to other species. For example, while retroviral enhancer-trap experiments in mice can be based on embryonic stem (ES) cell technology, this is not currently an option with other animals. Similarly, the germline transformation of Drosophila depends on the use of the P-element transposon, which does not jump in other genera. This article analyses the main characteristics of Tc1/mariner transposable elements, examines some of the factors that have contributed to their evolutionary success, and describes their potential, as well as their limitations, for transgenesis and insertional mutagenesis in diverse animals.
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Parasit Vectors,
2017]
Macrocyclic lactones (MLs), specifically the avermectins and milbemycins, are known for their effectiveness against a broad spectrum of disease-causing nematodes and arthropods in humans and animals. In most nematodes, drugs in this class induce paralysis, resulting in starvation, impaired ability to remain associated with their anatomical environment, and death of all life stages. Initially, this was also thought to be the ML mode of action against filarial nematodes, but researchers have not been able to validate these characteristic effects of immobilization/starvation of MLs in vitro, even at higher doses than are possible in vivo. Relatively recently, ML receptor sites exclusively located proximate to the excretory-secretory (ES) apparatus were identified in Brugia malayi microfilaria and an ML-induced suppression of secretory protein release by B. malayi microfilariae was demonstrated in vitro. It is hypothesized here that suppression of these ES proteins prevents the filarial worm from interfering with the host's complement cascade, reducing the ability of the parasite to evade the immune system. Live microfilariae and/or larvae, thus exposed, are attacked and presented to the host's innate immune mechanisms and are ultimately killed by the immune response, not the ML drug. These live, exposed filarial worms stimulate development of innate, cellular and humoral immune responses that when properly stimulated, are capable of clearing all larvae or microfilariae present in the host, regardless of their individual sensitivity to MLs. Additional research in this area can be expected to improve our understanding of the relationships among filarial worms, MLs, and the host immune system, which likely would have implications in filarial disease management in humans and animals.