Chartier NT et al. (2010) Med Sci (Paris) "[Mechanisms of asymmetric cell division: from model organisms to tumorigenesis]"

Hyenne V, Labbe JC, Chartier NT

[Med Sci (Paris), 2010]

Asymmetric cell division is the process by which a single cell gives rise to two different daughter cells. This process is important to generate cell diversity during the development of multicellular organisms, as well as for stem cell self-renewal in adults. Current knowledge on so-called cancer stem cells suggests that a loss of asymmetry during their division could lead to overproliferation and favour tumorigenesis, highlighting the importance of deciphering the mechanisms governing asymmetric cell division. Two mechanisms can lead to an asymmetric cell division: asymmetry can either be governed by proximity to a given cellular environment (or niche), in which case the mechanism is referred to as extrinsic, or the mother cell polarizes itself without external intervention, in which case the mechanism is referred to as intrinsic. In the last 20 years, our understanding of intrinsic mechanisms leading to asymmetric cell division has progressed, largely after studies carried out in model organisms such as the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster. These models allowed the identification of molecular complexes used by nearly all the cells that divide asymmetrically, including human cells. Here we review the main intrinsic mechanisms of asymmetric cell division as described in model organisms and discuss their relevance towards mammalian tumorigenesis.

Lok JB (2012) Parasitology "Nucleic acid transfection and transgenesis in parasitic nematodes."

Lok JB

[Parasitology, 2012]

Transgenesis is an essential tool for assessing gene function in any organism, and it is especially crucial for parasitic nematodes given the dwindling armamentarium of effective anthelmintics and the consequent need to validate essential molecular targets for new drugs and vaccines. Two of the major routes of gene delivery evaluated to date in parasitic nematodes, bombardment with DNA-coated microparticles and intragonadal microinjection of DNA constructs, draw upon experience with the free-living nematode Caenorhabditis elegans. Bombardment has been used to transiently transfect Ascaris suum, Brugia malayi and Litomosoides sigmodontis with both RNA and DNA. Microinjection has been used to achieve heritable transgenesis in Strongyloides stercoralis, S. ratti and Parastrongyloides trichosuri and for additional transient expression studies in B. malayi. A third route of gene delivery revisits a classic method involving DNA transfer facilitated by calcium-mediated permeabilization of recipient cells in developing B. malayi larvae and results in transgene inheritance through host and vector passage. Assembly of microinjected transgenes into multi-copy episomal arrays likely results in their transcriptional silencing in some parasitic nematodes. Methods such as transposon-mediated transgenesis that favour low-copy number chromosomal integration may remedy this impediment to establishing stable transgenic lines. In the future, stable transgenesis in parasitic nematodes could enable loss-of-function approaches by insertional mutagenesis, in situ expression of inhibitory double-stranded RNA or boosting RNAi susceptibility through heterologous expression of dsRNA processing and transport proteins.

Hoole D et al. (2004) Symp Soc Exp Biol "The role of apoptosis in non-mammalian host-parasite relationships."

Williams GT, Hoole D

[Symp Soc Exp Biol, 2004]

It is clear that the roles of apoptosis in the interactions between the parasite and their non-mammalian hosts are multifaceted and highly dependent on individual associations between the two organisms involved. Whilst there are instances where both organisms appear to gain from the apoptotic mechanism induced, in the majority of cases apoptosis appears to favour only one of the parties. In the instances when the parasite benefits, the apoptosis has been related to infectivity and virulence, an interruption of the killing mechanism of the host, and liberation of the pathogen. However, there are occasions where the apoptotic process benefits the host, as controlled cell death has been associated with limiting the pathogen population, parasite migration within the host and, in some instances, actually killing the invading organism. Apoptosis thus appears to play several fundamental roles within the host-parasite relationship which is ultimately reflected in an effect on the host population either mediated through an alteration in host fecundity or reduction in host numbers. The next decade promises to be both exciting and productive with respect to our knowledge of the relationship between apoptosis in non-mammalian animals and infection. Over the last few years the information obtained from studies on the apoptotic process in mammals and invertebrates (i.e. C. elegans and Drosophila) have been effectively used to increase our understanding of the apoptotic process in other animals such as insects, fish and amphibians. Such knowledge has paved the way for extensive studies on the effect of infections to be carried out.

Hartmann S et al. (2003) Int J Parasitol "Modulation of host immune responses by nematode cystatins."

Lucius R, Hartmann S

[Int J Parasitol, 2003]

Parasitic nematodes, living in the intestinal tract or within tissues of theirs hosts, are constantly exposed to an array of immune effector mechanisms. One strategy to cope with the immune response is the release of immunomodulatory components that block effector mechanisms or interact with the cytokine network. Among the secreted nematode immunomodulators, cysteine protease inhibitors (cystatins) are shown to be of major importance. Nematode cystatins inhibit, among others, proteases involved in antigen processing and presentation, which leads to a reduction of T cell responses. At the same time nematode cystatins modulate cytokine responses, the most prominent trait being the upregulation of IL-10, a Th2 cytokine, by macrophages. In this situation, IL-10 leads among others to downregulation of costimulatory surface molecules of macrophages. These properties contribute to induction of an anti-inflammatory environment, concomitant with a strong inhibition of cellular proliferation. This setting is believed to favour the survival of worms. An opposite activity of nematode cystatins is the upregulation of production of inducible nitric oxide by IFN-gamma activated macrophages, an intrinsic property of natural cysteine protease inhibitors. This shows that these proteins can act as proinflammatory molecules under certain circumstances. A comparison of the immunomodulatory effects of cystatins of filarial nematodes with homologous proteins of the free-living nematode Caenorhabditis elegans revealed distinct differences. Caenorhabditis elegans cystatins induce the production of the Th1 cytokine IL-12, in contrast to filarial cystatins that upregulate IL-10. Caenorhabditis elegans cystatins hardly inhibit cellular proliferation. These data suggest that cystatins of parasitic nematodes have multiple, specific capacities for immunomodulation, acting in parallel on different immune effector mechanisms. Elucidation of the mechanisms involved might be useful in the development of immunotherapeutic reagents in the future.