Biology subjects

Andrieu, M.

Publications and source records attributed to Andrieu, M..

5 recordsLinked to original sources

bioRxiv2025

Spatial and Multiomic profiling of muscle regeneration dynamics in Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a pediatric degenerative myopathy caused by the absence of functional dystrophin. As a result, DMD muscles exhibit compromised myofiber integrity and increased susceptibility to mechanical damage. In early disease stages, muscles undergo repeated cycles of degeneration and regeneration; over time, however, this regenerative capacity declines, leading to the gradual replacement of muscle tissue with fat and fibrosis. While several signaling pathways have been identified as deregulated in dystrophic muscle, the cellular and molecular mechanisms underlying this regenerative exhaustion remain to be fully elucidated. To address this, we constructed a comprehensive cellular atlas of human dystrophic muscle using high-resolution spatial transcriptomics (Visium HD), capturing the cellular crosstalk within regenerative regions. Cell-to-cell communication analysis revealed activation of Notch signaling mediated by NOTCH3 in activated satellite cells. Immunostaining confirmed elevated NOTCH3 expression in both DMD patient samples and in the mdx mouse model at late disease stages. Silencing of NOTCH3 in primary myoblasts improved myogenic differentiation, pinpointing NOTCH3-mediated signaling as a contributor to regeneration impairment. To further dissect the dynamics of regeneration and infer the gene regulatory networks governing myogenic differentiation, we integrated paired snRNA-seq and snATAC-seq data from young, adult, and aged mdx mice. This analysis identified GLIS3 upregulation as an additional barrier to effective myogenesis. GLIS3 displayed an overall increase in dystrophic muscles, while silencing experiments enhanced differentiation in myoblasts. Together, our work reveals intrinsic defects in the dystrophic stem cell compartment that emerge during disease progression and hinder the execution of the myogenic program. These findings suggest NOTCH3 and GLIS3 as potential therapeutic targets to enhance regeneration and maintain muscle integrity in DMD. This study provides a high-resolution map of the dystrophic regenerative landscape and offers a valuable resource for future translational research.

cell biology↗

bioRxiv2025

A Catalytically Inactive Protein Kinase C alpha Mutation Drives Chordoid Glioma by Pathway Rewiring

Abstract SummaryChordoid glioma (ChG) is a rare, low-grade brain tumor characterized by a novel recurrent point mutation, D463H, in the kinase domain of protein kinase C alpha (PKC). The mutation is invariably an Asp to His substitution, suggesting it endows a unique function beyond catalytic inactivation associated with other cancer-associated PKC mutations. Here we use in vitro and in cellulo activity assays to show that PKCD463H is catalytically inactive, functions as a dominant-negative mutant to suppress endogenous PKC and uniquely rewires the cellular interactome. Specifically, phosphoproteomic, proximity labeling, and co-immunoprecipitation mass-spectrometry data from cells overexpressing PKCD463H identify altered phosphorylation of substrates and binding to multiple proteins involved in cell-cell junctions compared to WT enzyme. Lastly, single nuclei RNAseq reveals that ChG derives from specialized tanycytes. Our data suggest that this disease-defining, fully penetrant mutation promotes neomorphic non-catalytic scaffolding to impair cell junction function.

molecular biology↗

bioRxiv2023

The double-edged role of FASII regulator FabT in Streptococcus pyogenes infection

In Streptococcus pyogenes, the type II fatty acid (FA) synthesis pathway FASII is feedback- controlled by the FabT repressor bound to an acyl-Acyl carrier protein. Despite FabT defects being linked to reduced virulence in animal models, spontaneous fabT mutants arise in vivo. To resolve this paradox, we characterized the conditions and mechanisms that require FabT activity, and those that promote fabT mutant emergence. The primary fabT mutant defect is energy dissipation: specific nutrients are consumed, but the mutant fails to grow on human tissue, cells, or cell filtrates where nutrients are limited. These features explain the FabT requirement during infection. Conversely, fabT mutants exhibited a marked growth advantage over the wild-type in biotopes rich in saturated FAs. fabT mutants emerge in this context, where continued FASII activity prevented environmental FA incorporation. An ex vivo muscle model demonstrated that wild-type S. pyogenes was inhibited, while fabT mutant growth was stimulated, but conditional to FASII activity. Our findings elucidate the rationale for emerging fabT mutants that improve survival in lipid-rich biotopes, but lead to a genetic impasse for infection.

microbiology↗

bioRxiv2021

Synthetic deconstruction of hunchback regulation by Bicoid

For over 40 years, the Bicoid-hunchback (Bcd-hb) system in the fruit fly embryo has been used as the model to study how positional information in morphogen concentration gradients is robustly translated into step-like responses. A body of quantitative comparisons between theory and experiment have since questioned the initial paradigm that the sharp hb transcription pattern emerges solely from diffusive biochemical interactions between the Bicoid transcription factor and the gene promoter region. Several alternative mechanisms have been proposed, such as additional sources of positional information, positive feedback from Hb proteins or out-of-equilibrium transcription activation. By using the MS2-MCP RNA-tagging system and analysing in real time, the transcription dynamics of synthetic reporters for Bicoid and/or its two partners Zelda and Hunchback, we show that all the hb expression pattern features and temporal dynamics are compatible with an equilibrium model with a short decay length Bicoid activity gradient as a sole source of positional information. Meanwhile, Bicoids partners speed-up the process by different means: Zelda lowers the Bicoid concentration threshold required for transcriptional activation while Hunchback reduces burstiness and increases the polymerase firing rate.

developmental biology↗

bioRxiv2021

Extreme longevity of highly fecund termite queens achieved by mitochondrial and insulin upregulation without harmful lipid signatures or accumulation

Kings and queens of eusocial termites can live for decades, while queens sustain a nearly maximal fertility. To investigate the molecular mechanisms underlying their long lifespan, we carried out transcriptomics, lipidomics and metabolomics in Macrotermes natalensis on sterile short-lived workers, long-lived kings and five stages spanning twenty years of adult queen maturation. Reproductives share gene expression differences from workers in agreement with a reduction of several aging-related processes, involving upregulation of DNA damage repair and mitochondrial functions. Anti-oxidant gene expression is downregulated, while peroxidability of membranes in queens decreases. Against expectations, we observed an upregulated gene expression in fat bodies of reproductives of several components of the IIS pathway, including an insulin-like peptide, Ilp9. This pattern does not lead to deleterious fat storage in physogastric queens, while simple sugars dominate in their hemolymph and large amounts of resources are allocated towards oogenesis. Our findings support the notion that all processes causing aging need to be addressed simultaneously in order to prevent it.

molecular biology↗