Biology subjects

Dalle, C.

Publications and source records attributed to Dalle, C..

4 recordsLinked to original sources

bioRxiv2025

Tunable nucleofugality in carbamoyl-bearing covalent cholinesterase inhibitors

A handful of carbamate warheads is utilised in chemical biology to target serine hydrolases. The following case study on cholinesterases is the first comprehensive structure-reactivity exploration of the carbamoyl warhead, rather than one-target-oriented structure-activity study, with in-depth profiling of diverse halogen, chalcogen, and nitrogen-based leaving groups (nucleofuges) that can tune warhead reactivity. With computational tools we correlated the experimentally observed reactivities with steric and electronic factors of the investigated warheads. QM/MM simulations considering the enzymatic environment explained how substitution of carbon for nitrogen in the leaving groups of compounds 26 and 28 through resonance stabilisation, inductive bond polarization, and acidity amplification lowered the reaction barrier and increased the reaction rate >360 million times, making compound 28 a covalent inhibitor. Our findings underline the complexity of covalent inhibition and demonstrate that multiple complementary methods are required to interpret and predict covalent behaviour. Additionally, even though carbamates typically act as slow substrates, we were able to slow down decarbamoylation to a point where inhibition became de facto irreversible. The most interesting O-isoxazol-3-yl carbamate warhead was further profiled against the wider human proteome and showed low off-target reactivity, making it useful in further drug discovery. By establishing structure-reactivity principles for carbamoyl warhead, this study provides a generalisable framework for the development of selective covalent inhibitors and activity-based probes across diverse targets.

pharmacology and toxicology↗

bioRxiv2025

Mosaic human cortical organoids model mTOR-related focal cortical dysplasia through DEPDC5 loss-of-function

Focal cortical dysplasia type II (FCDII), a leading cause of pediatric drug-resistant focal epilepsy, results from brain somatic variants in genes of the mTOR pathway, including germline and somatic second-hit loss-of-function variants in the mTOR repressor DEPDC5. Here, we investigated the effects of mosaic DEPDC5 two-hit variants on cortical development and neuronal activity using patient-derived human cortical organoids (hCOs). Mosaic hCOs displayed increased mTOR activity and altered neural rosette densities, which were both rescued by treatment with the mTOR inhibitor rapamycin. In addition, mosaic hCOs presented dysmorphic-like neurons and increased neuronal excitability, recapitulating FCDII pathology. Longitudinal single-cell transcriptomics at three developmental stages revealed altered neuronal differentiation, dysregulated expression of genes associated with the Notch and Wnt pathways in neural progenitors, and of synaptic- and epilepsy-associated genes in excitatory neurons. We further identified cell-autonomous alterations in metabolism and translation in mosaic two-hit hCOs. This study provides novel insights into the consequences of mosaic biallelic DEPDC5 deficiency on corticogenesis in the context of FCDII, highlighting both autonomous and non-cell autonomous effects.

neuroscience↗

bioRxiv2025

Multifaceted conserved functions of Notch during post-embryonic neurogenesis in the annelid Platynereis

Notch signaling is an evolutionarily conserved pathway known to orchestrate neurogenesis by regulating the transition of progenitor cells to differentiated neurons and glia, as well as by directing neurite outgrowth and axon guidance in many species. Although extensively studied in vertebrates and ecdysozoans, the role of Notch in spiralians (including mollusks, annelids or flatworms) remains largely unexplored, limiting our understanding of its conserved functions across bilaterians. In this study, we focus on the segmented annelid Platynereis dumerilii, a model organism in neurobiology and regeneration, to investigate Notch signaling functions during post-embryonic developmental processes. We show that Notch pathway components are expressed in neurogenic territories during both posterior elongation and regeneration, two processes requiring sustained neurogenesis. Through chemical inhibitions of the pathway and RNA-seq profiling, we demonstrate that Notch signaling regulates neural progenitor specification, differentiation, and overall neurogenic balance in the regenerating and elongating posterior part. Moreover, disruption of Notch activity leads to severe defects in pygidial and central nervous system organization, including abnormal axon guidance and impaired neurite outgrowth. Altogether, our results support the hypothesis that Notch has multifaceted conserved functions in neurogenesis across bilaterians, shedding light on the ancestral functions of this critical pathway.

developmental biology↗

bioRxiv2023

Transcriptomic landscape of posterior regeneration in the annelid Platynereis dumerilii

Background: Restorative regeneration, the capacity to reform a lost body part following amputation or injury, is an important and still poorly understood process in animals. Annelids, or segmented worms, show amazing regenerative capabilities, and as such are a crucial group to investigate. Elucidating the molecular mechanisms that underpin regeneration in this major group remains a key goal. Among annelids, the nereididae Platynereis dumerilii (re)emerged recently as a front-line regeneration model. Following amputation of its posterior part, Platynereis worms can regenerate both differentiated tissues of their terminal part as well as a growth zone that contains putative stem cells. While this regeneration process follows specific and reproducible stages that have been well characterized, the transcriptomic landscape of these stages remains to be uncovered. Results: We generated a high quality de novo Reference transcriptome for the annelid Platynereis dumerilii. To do so, we produced and analyzed three RNA-sequencing datasets, encompassing five stages of posterior regeneration, along with blastema stages and non-amputated tissues as controls. We included these regeneration RNA-seq datasets, as well as embryonic and tissue-specific datasets from the literature to produce a Reference transcriptome. We used this Reference transcriptome to perform in depth analyzes of RNA-seq data during the course of regeneration to reveal the important dynamics of the gene expression, process with thousands of genes differentially expressed between stages, as well as unique and specific genes expression at each regeneration stage. The study of these genes highlighted the importance of the nervous system at both early and late stages of regeneration, as well as the enrichment of RNA-binding proteins (RBPs) during almost the entire regeneration process. Conclusions: In this study, we provided a high-quality de novo Reference transcriptome for the annelid Platynereis that is useful for investigating various developmental processes, including regeneration. Our extensive stage-specific transcriptional analysis during the course of posterior regeneration shed light upon major molecular mechanisms and pathways, and will foster many specific studies in the future.

genomics↗