Acquired resistance to monepantel in C. elegans: What about parasitic nematodes?

In 2008, Novartis Animal Health developed a new class of anthelmintics, the amino-acetonitrile derivatives (AAD) of which monepantel is the most prominent compound. Monepantel was designed for the treatment of sheep against the parasitic nematode Haemonchus contortus. Because monepantel acts through a different mechanism, it is effective against nematodes that have acquired resistance to long-standing anthelmintics.

acr-23 Encodes a monepantel-sensitive channel in Caenorhabditis elegans.

Monepantel is a member of the recently identified class of anthelmintics known as the amino-acetonitrile derivatives (AADs). Monepantel controls all major gastro-intestinal nematodes in sheep including those that are resistant to the classical anthelmintics. Previous studies have shown that the Caenorhabditis elegans acr-23 and the Haemonchus contortus Hco-mptl-1 genes may be prominent targets of monepantel.

Sex determination in the Caenorhabditis elegans germline.

How is sex determined? In the animal kingdom, there are diverse sets of mechanisms for determining organismal sex, with the predominant ones being chromosomally based, either a dominant-acting sex chromosome or the ratio of the number of X chromosome to autosomes, which lead to oocyte-producing females and sperm-producing males. The resulting germline sexual phenotype is often the logical consequence of somatic sex determination. In this respect however, the Caenorhabditis elegans hermaphrodite is different from mammals and Drosophila.

The sperm-oocyte switch in the C. elegans hermaphrodite is controlled through steady-state levels of the fem-3 mRNA.

Post-transcriptional control regulates many aspects of germline development in the Caenorhabditis elegans hermaphrodite. This nematode switches from spermatogenesis to oogenesis and is, therefore, capable of self-fertilization. This sperm-oocyte switch requires 3' UTR-mediated repression of the fem-3 mRNA.

Role of the C. elegans U2 snRNP protein MOG-2 in sex determination, meiosis, and splice site selection.

In Caenorhabditis elegans, germ cells develop as spermatids in the larva and as oocytes in the adult. Such fundamentally different gametes are produced through a fine-tuned balance between feminizing and masculinizing genes. For example, the switch to oogenesis requires repression of the fem-3 mRNA through the mog genes.

Different Mi-2 complexes for various developmental functions in Caenorhabditis elegans.

Biochemical purifications from mammalian cells and Xenopus oocytes revealed that vertebrate Mi-2 proteins reside in multisubunit NuRD (Nucleosome Remodeling and Deacetylase) complexes. Since all NuRD subunits are highly conserved in the genomes of C. elegans and Drosophila, it was suggested that NuRD complexes also exist in invertebrates.

The C. elegans sex determination protein MOG-3 functions in meiosis and binds to the CSL co-repressor CIR-1.

In the germ line of the Caenorhabditis elegans hermaphrodite, nuclei either proliferate through mitosis or initiate meiosis, finally differentiating as spermatids or oocytes. The production of oocytes requires repression of the fem-3 mRNA by cytoplasmic FBF and nuclear MOG proteins. Here we report the identification of the sex determining gene mog-3 and show that in addition to its role in gamete sex determination, it is necessary for meiosis by acting downstream of GLP-1/Notch.

The DEAD-box protein MEL-46 is required in the germ line of the nematode Caenorhabditis elegans.

Background: In the hermaphrodite of the nematode Caenorhabditis elegans, the first germ cells differentiate as sperm. Later the germ line switches to the production of oocytes. This process requires the activity of a genetic regulatory network that includes among others the fem, fog and mog genes.

Inactivation of the autophagy gene bec-1 triggers apoptotic cell death in C. elegans.

Programmed cell death (PCD) is an essential and highly orchestrated process that plays a major role in morphogenesis and tissue homeostasis during development. In humans, defects in regulation or execution of cell death lead to diabetes, neurodegenerative disorders, and cancer. Two major types of PCD have been distinguished: the caspase-mediated process of apoptosis and the caspase-independent process involving autophagy.

Roles of the C. elegans cyclophilin-like protein MOG-6 in MEP-1 binding and germline fates.

The switch from spermatogenesis to oogenesis in the Caenorhabditis elegans hermaphrodite requires mog-6, which post-transcriptionally represses the fem-3 RNA. In this study, we show that mog-6 codes for a divergent nuclear cyclophilin, in that a conserved domain is not required for its function in the sperm-oocyte switch. MOG-6 binds to the nuclear zinc finger protein MEP-1 through two separate domains that are essential for the role of MOG-6 in the sperm-oocyte switch.

The MEP-1 zinc-finger protein acts with MOG DEAH box proteins to control gene expression via the fem-3 3' untranslated region in Caenorhabditis elegans.

Cell fates in the Caenorhabditis elegans germline are regulated, at least in part, at the posttranscriptional level. For example, the switch from spermatogenesis to oogenesis in the hermaphrodite relies on posttranscriptional repression of the fem-3 mRNA via its 3' untranslated region (UTR). Previous studies identified three DEAH box proteins, MOG-1, MOG-4, and MOG-5, that are critical for the fem-3 3' UTR control.