Biology subjects

Charvet, C.

Publications and source records attributed to Charvet, C..

5 recordsLinked to original sources

bioRxiv2026

Potential nematicides identified through targeted in vivo screening of a 5-HT-gated chloride channel, MOD-1

New approaches to mitigate the reduction of crop yields by plant parasitic nematodes are needed in the face of increasing concerns of the impact of nematicides on precious ecosystems. One approach is to target receptors in the parasitic nematode that are vital for their survival that less widely expressed in non-target organisms. Nematodes express a phylogenetically restricted 5-HT-gated chloride channel, MOD-1, activation of which causes paralysis in Caenorhabditis elegans. We show that MOD-1 is expressed in the motor nervous system of the plant parasitic nematode Globodera pallida and its functional characterisation is validated by 5-HT activation when reconstituted in Xenopus laevis oocytes. To evaluate MOD-1 as a nematicide target we utilised a previously described platform called PhaGeM4 for PharmacoGenetic targeting of M4 neurone in which MOD-1 is expressed in transgenic C. elegans and nematode development in the face of MOD-1 chemical modulation is tracked. We screened Pathogen Box, a chemical library of 400 diverse drug-like molecules, using PhaGeM4. This identified 10 putative hits for C. elegans MOD-1. These hits were pursued through a sequential, iterative pipeline encompassing mod-1 dependent C. elegans motility and G.pallida motility assays in combination with pharmacological interrogation of G. pallida mod-1 in PhaGeM4. This approach highlights 3 compounds with a mod-1 dependent action (quipazine, our benchmark compound; MMV687251, a vancomycin-like compound; MMV688774, an antifungal with common name posaconazole) and one compound that acts through an undetermined target (MMV002816, also known as the antifilarial drug, diethylcarbamazine). Each of these compounds had a significant inhibitory effect on G. pallida J2 root invasion. Overall, this lends confidence that the PhaGeM4 screening platform can delivery new chemical leads for crop protection and highlights four new chemistries of interest. More generally, this approach could be applied to other ligand-gated ion channels of interest as targets.

pharmacology and toxicology↗

bioRxiv2025

The Dirofilaria immitis unc-49 gene encodes a pharmacologically unique cys-loop GABA receptor

Nematode cys-loop GABA receptors play important roles in movement and locomotion. GABA receptors encoded by unc-49 appear to be widespread in nematode genomes including parasitic nematodes but are poorly characterized in filarial parasites. Dirofilaria immitis is a filarial parasite responsible for heartworm disease in dogs. Macrocyclic lactones are widely used to prevent heartworm infection. However, like many anthelmintics, resistance has emerged and new solutions are needed including the discovery of new anthelmintic drug targets. In this study, we report the isolation of two unc-49 subunit mRNAs (unc-49b and unc-49c) from the canine parasitic nematode D. immitis. When expressed in Xenopus oocytes, Dim-UNC-49B formed a functional homomeric GABA-gated channel, whereas Dim-UNC-49C did not. We further demonstrated that Dim-UNC-49B and Dim-UNC-49C gave rise to a functional heteromeric channel. Pharmacological characterization of these receptors and cross-species co-expression with UNC-49 subunits from the parasitic nematode Haemonchus contortus showed some unique properties compared to the same receptors characterized from other nematodes. These results revealed new properties of UNC-49 receptors in filarial worms.

pharmacology and toxicology↗

bioRxiv2025

How Ikaros and Aiolos homo- and heterodimers drive gene expression to ensure B cell development

Ikaros family transcription factors (TF) are major regulators of cell differentiation and function. They function as homo- and heterodimers, but the contribution of specific dimers to gene regulation is unknown. We investigated the function of Ikaros-Ikaros, Ikaros-Aiolos and Aiolos-Aiolos in B cell development, and show that the dimers are not equivalent. Ikaros homodimers are required in proB and large preB cells where they bind and regulate the expression of a surprisingly small number of genes related to cell adhesion and migration, predominantly as transcriptional repressors. In contrast, Ikaros-Aiolos heterodimers and Aiolos homodimers are required in small preB and immature IgM+ B cells to regulate 10-fold larger target gene repertoires involved in B cell receptor signaling and immune functions. Aiolos-containing dimers act mainly as repressors in small preB cells but activators in immature B cells, where Aiolos-Aiolos antagonizes Ikaros-Ikaros. Mechanistically, Aiolos binds more GGAA motifs with different flanking nucleotides than Ikaros, which depends on a single amino acid difference in zinc finger 3 of its DNA binding domain. These results illustrate how homo- and heterodimerization of homologous TF proteins can markedly impact binding specificity, target gene response and pathway modulation in cells of the same lineage.

immunology↗

bioRxiv2018

Evolution of connections and cell types: integrating diffusion MR tractography with gene expression data highlights increased cortico-cortical projections in primates

Diffusion MR tractography permits investigating the three-dimensional structure of cortical pathways as interwoven paths across the entire brain. We use high-resolution scans from diffusion spectrum imaging and high angular resolution diffusion imaging to investigate the evolution of cortical pathways within the euarchontoglire (i.e., primates, rodents) lineage. More specifically, we compare cortical fiber pathways between macaques (Macaca mulatta), marmosets (Callithrix jachus), and rodents (mice, Mus musculus). We integrate these observations with comparative analyses of Neurofilament heavy polypeptide (NEFH) expression across the cortex of mice and primates. We chose these species because their phylogenetic position serves to trace the early evolutionary history of the human brain. Our comparative analysis from diffusion MR tractography and NEFH expression demonstrates that the examined primates deviate from mice in possessing increased long-range cross-cortical projections, many of which course across the anterior to posterior axis of the cortex. Our study shows that integrating gene expression data with diffusion MR data is an effective approach in identifying variation in connectivity patterns between species. The expansion of cortico-cortical pathways and increased anterior to posterior cortical integration can be traced back to an extension of neurogenetic schedules during development in primates.

neuroscience↗

bioRxiv2018

Comparing adult hippocampal neurogenesis across species: translating time to predict the tempo in humans

Comparison of neurodevelopmental sequences between species whose initial period of brain organization may vary from one hundred days to one thousand days, and whose progress is intrinsically nonlinear presents large challenges in normalization. Comparing adult timelines when lifespans stretch from one year to seventy-five, when underlying cellular mechanisms under scrutiny do not scale similarly, presents challenges to simple detection and comparison. The question of adult hippocampal neurogenesis has generated numerous controversies regarding its simple presence or absence in humans versus rodents, whether it is best described as the tail of a distribution centered on early neural development, or is several distinct processes. In addition, adult neurogenesis may have substantially changed in evolutionary time in different taxonomic groups. Here we extend and adapt a model of the cross-species transformation of early neurodevelopmental events which presently reaches up to the equivalent of the third human postnatal year for 18 mammalian species (www.translatingtime.net) to address questions relevant to hippocampal neurogenesis, which permit extending the database to adolescence or perhaps to the whole lifespan. We acquired quantitative data delimiting the envelope of hippocampal neurogenesis from cell cycle markers (i.e., Ki67, DCX) and RNA sequencing data for two primates (macaque, humans) and two rodents (rat, mouse). To improve species coverage in primates, we gathered the same data from marmosets (Callithrix jacchus), but additionally gathered data on a number of developmental milestones to find equivalent developmental time points between marmosets and other species. When all species are so modeled, and represented in a common time frame, the envelopes of hippocampal neurogenesis are essentially superimposable. Early developmental events involving the olfactory and limbic system start and conclude possibly slightly early in primates than rodents, and we find a comparable early conclusion of primate hippocampal neurogenesis (as assessed by the relative number of Ki67 cells) suggesting a plateau to low levels at approximately 2 years of age in humans. Marmosets show equivalent patterns within neurodevelopment, but unlike macaque and humans may have wholesale delay in the initiation of neurodevelopment processes previously observed in some precocial mammals such as the guinea pig and multiple large ungulates.

neuroscience↗