Biology subjects

Andrieux, A.

Publications and source records attributed to Andrieux, A..

13 recordsLinked to original sources

bioRxiv2026

Temporal tuning of actin nucleation by the repurposed DNA repair complex RAD51/fignl1 encodes distinct axon guidance decisions

Axon guidance is essential for neural circuit assembly and function. While much of the repertoire of guidance cues and receptors is known, its limited diversity cannot fully explain the remarkable complexity of the brain connectome. How temporally ordered, context-dependent intrinsic programs shape the diversity of axonal responses to guidance signals remains poorly understood. We reveal how non-canonical Wnt5a signalling repurposes the DNA repair complex RAD51/fignl1 as a downstream integrator to control retinal ganglion cell axon decision-making at the midline. We demonstrate that differential RAD51/fignl1 expression and interaction dynamics between ipsilateral and contralateral axons tunes the magnitude and temporal dynamics of F-actin nucleation, thereby encoding their trajectory choice. Our findings establish temporal control of cytoskeletal dynamics as a key determinant of axon decision-making and thereby a fundamental layer of circuit wiring. They provide a potential mechanistic framework linking mutations in the DNA repair gene RAD51 to neurodevelopmental disorders with midline guidance defects.

neuroscience↗

bioRxiv2026

VASH1 phosphorylation regulates tubulin detyrosination via CNP/PRKG1α signaling in DRG neurons.

Functional neuronal circuit formation requires precise regulation of axon growth and branching through dynamic cytoskeletal remodeling. Although microtubule detyrosination/re-tyrosination critically controls microtubule dynamics, how extracellular signals regulate this process remains unclear. Here, we identify a direct link between C-type natriuretic peptide, protein kinase cGMP-dependent 1 (CNP/cGMP/PRKG1) signaling and microtubule detyrosination in dorsal root ganglion (DRG) neurons. CNP stimulation induces growth cone enlargement, increases tyrosinated tubulin within growth cones, and reduces detyrosinated tubulin along axons, effects abolished by PRKG1 inhibition. Pharmacological inhibition or genetic deletion of the detyrosinating enzyme VASH1 phenocopies CNP-induced growth cone remodeling. In vitro kinase assays identify VASH1 as a direct PRKG1 substrate and reveal a specific C-terminal serine phosphorylation site (serine 337) that suppresses VASH1-SVBP microtubule association and detyrosination activity. Together, these findings establish VASH1-SVBP as a key downstream effector linking extracellular guidance signaling to microtubule remodeling during DRG neuronal development.

cell biology↗

bioRxiv2025

Chemical inhibition of SUMOylation activates the FSHD locus

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive and debilitating muscle disease for which no cure currently exists. In the majority of cases, FSHD is associated with the contraction of the D4Z4 macrosatellite repeat array at the 4q35 locus, leading to the inappropriate activation of DUX4, normally expressed during early embryogenesis. In FSHD, the genetic contraction is accompanied by hypomethylation of the D4Z4 array. Although a connection between DNA hypomethylation and DUX4 expression has been suggested, the precise mechanisms that regulate DUX4 transcription remain incompletely defined. The post-translational modification by SUMO was shown previously to repress the expression of Dux, the DUX4 homolog, in mouse embryonic stem cells. Based on these findings, we explored here the contribution of SUMOylation in the regulation of DUX4 in human muscle cells. We demonstrate that TAK981 (subasumstat), a selective SUMOylation inhibitor, promotes transcriptional reprogramming of the 4q35 locus and induces DUX4 expression. Importantly, this activation occurs independently of changes in DNA methylation or SMCHD1 ATPase activity. Our findings identify SUMOylation inhibition as a novel regulatory pathway driving DUX4 expression. This work uncovers the importance of SUMOylation in the epigenetic control of the 4q35 locus and DUX4 transcription, providing a potential therapeutic strategy to modulate DUX4 expression in FSHD.

genetics↗

bioRxiv2025

Uromyces plumbarius first reported on Oenothera lindheimeri in Europe with widespread distribution and association with the rust hyperparasite Sphaerellopsis sp.

The rust fungus Uromyces plumbarius Peck was reported in Europe for the first time on Oenothera lindheimeri (Engelm. & A. Gray) W.L. Wagner & Hoch (Lindheimers beeblossom), a highly popular ornamental plant widely cultivated since the 2000s. The fungus was found in 11 locations across France and two locations in the Netherlands. The identification was based on an analysis of morphological characteristics and 28S rDNA sequences. The pathogenicity was confirmed through reinoculation using fresh urediniospores. This represents the first record of U. plumbarius outside its native range in North America. Its widespread distribution in France appears to result from rapid dissemination, likely facilitated by the plant trade between nursery gardeners. The discovery of U. plumbarius was accompanied by the detection of the hyperparasitic fungus Sphaerellopsis sp. and fungivorous larvae of Mycodiplosis sp.--two native, non-specific natural enemies which may play a role in limiting the impact of rust infections.

microbiology↗

bioRxiv2025

Long-lasting coexistence of multiple asexual lineages alongside their sexual counterparts in a fungal plant pathogen

Sexual-to-asexual transitions within species are crucial for understanding reproductive evolution, yet the coexistence of both modes of fungal species in the same environment is poorly documented. Here, we report this transition in a plant pathogen species that coexists within the same geographical environment. Our biological model is the poplar rust fungus Melampsora larici-populina, which displays a complex life cycle typical of rust fungi (Pucciniales). It alternates between two unrelated hosts to complete an obligate sexual life cycle once a year. We conducted a comprehensive population genetic analysis, using 21 microsatellite markers and data from 2,122 individuals gathered over 30 years from various locations in France. Our results demonstrate the existence of many distinct lineages that reproduce asexually through the years, skipping the sexual phase. Clustering analysis identified a group of multilocus lineages that displayed all hallmarks of the genetic consequences of asexual reproduction, including highly negative and large variance among loci of the inbreeding coefficient (FIS). This indirect evidence for asexual reproduction was confirmed by the direct observation of these asexual lineages being repeatedly sampled across multiple years. This result demonstrates the coexistence of these lineages with their sexual counterparts in the same ecological niche, challenging conventional assumptions about geographical sorting of reproductive modes. These considerations are of paramount importance for understanding the contemporary evolution of major pathogen species. This switch from sexual to asexual reproduction has contributed to devastating epidemics worldwide.

evolutionary biology↗

bioRxiv2025

The Mn-motif protein MAP6d1 assembles ciliary doublet microtubules

Most eukaryotic cells have cilia that serve vital functions in sensing, signaling, motility. The core architecture of cilia is an array of microtubule doublets, which consist of a complete A-tubule and an incomplete B-tubule. The mechanisms governing the assembly of this complex structure remain poorly understood. Here, using total internal reflection fluorescence microscopy and cryo-electron tomography, we investigate the role of MAP6d1, a brain-specific protein containing microtubule lumen-targeting Mn-motifs. We show that MAP6d1 assembles stable microtubule doublets by recruiting tubulin dimers onto the lattice of the A-tubule to initiate the nucleation of the B-tubule. MAP6d1 also promotes the formation of luminal protofilaments in singlet and doublet microtubules, a previously undescribed phenomenon that likely enhances microtubule stability. In neurons, MAP6d1 localises to the proximal part of primary cilia via its Mn-motif, with its loss resulting in shortened cilia, a characteristic of ciliopathies. MAP6d1 is thus the first microtubule-associated protein found to assemble microtubule doublets, uncovering new functions for Mn-motif proteins in neurons.

cell biology↗

bioRxiv2022

Approximate Bayesian Computation applied to time series of population genetic data disentangles rapid genetic changes and demographic variations in a pathogen population

Adaptation can occur at remarkably short timescales in natural populations, leading to drastic changes in phenotypes and genotype frequencies over a few generations only. The inference of demographic parameters can allow understanding how evolutionary forces interact and shape the genetic trajectories of populations during rapid adaptation. Here we propose a new Approximate Bayesian Computation (ABC) framework that couples a forward and individual-based model with temporal genetic data to disentangle genetic changes and demographic variations in a case of rapid adaptation. We test the accuracy of our inferential framework and evaluate the benefit of considering the full trajectory compared to few time samples. Theoretical investigations demonstrate high accuracy in both model and parameter estimations, even if a strong thinning is applied to time series data. Then, we apply our ABC inferential framework to empirical data describing the population genetics changes of the poplar rust pathogen following a major event of resistance overcoming. We successfully estimate key demographic and genetic parameters, including the proportion of resistant hosts deployed in the landscape and the level of standing genetic variation from which selection occurred. Inferred values are in accordance with our empirical knowledge of this biological system. This new inferential framework, which contrasts with coalescent-based ABC analyses, is promising for a better understanding of evolutionary trajectories of populations subjected to rapid adaptation.

evolutionary biology↗

bioRxiv2021

Impaired α-tubulin re-tyrosination leads to synaptic dysfunction and is a feature of Alzheimer's disease

In neurons, dynamic microtubules play regulatory roles in neurotransmission and synaptic plasticity. While stable microtubules contain detyrosinated tubulin, dynamic microtubules are composed of tyrosinated tubulin, suggesting that the tubulin tyrosination/detyrosination (Tyr/deTyr) cycle modulates microtubule dynamics and synaptic function. In the Tyr/deTyr cycle, the C-terminal tyrosine of -tubulin is re-added by tubulin-tyrosine-ligase (TTL). Here we show that TTL+/- mice exhibit decreased tyrosinated microtubules, synaptic plasticity and memory deficits, and that reduced TTL expression is a feature of sporadic and familial Alzheimers disease (AD), with human APPV717I neurons having less dynamic microtubules. We find that spines visited by dynamic microtubules are more resistant to Amyloid{beta}1-42 and that TTL, by promoting microtubule entry into spines, prevents A{beta}1-42-induced spine pruning. Our results demonstrate that the Tyr/deTyr cycle regulates synaptic plasticity, is protective against spine injury, and that tubulin re-tyrosination is lost in AD, providing evidence that a defective Tyr/deTyr cycle may contribute to neurodegeneration.

neuroscience↗

bioRxiv2021

Genomic signatures of a major adaptive event in the pathogenic fungus Melampsora larici-populina

BackgroundThe recent availability of genome-wide sequencing techniques has allowed systematic screening for molecular signatures of adaptation, including in non-model organisms. Host-pathogen interactions constitute good models due to the strong selective pressures that they entail. We focused on an adaptive event which affected the poplar rust fungus Melampsora larici-populina when it overcame a resistance gene borne by its host, cultivated poplar. Based on 76 virulent and avirulent isolates framing narrowly the estimated date of the adaptive event, we examined the molecular signatures of selection. ResultsUsing an array of genome scan methods, we detected a single locus exhibiting a consistent pattern suggestive of a selective sweep in virulent individuals (excess of differentiation between virulent and avirulent samples, linkage disequilibrium, genotype-phenotype statistical association and long-range haplotypes). Our study pinpoints a single gene and further a single amino acid replacement which may have allowed the adaptive event. Although the selective sweep occurred only four years earlier, it does not seem to have affected genome diversity further than the immediate vicinity of the causal locus. ConclusionsOur results suggest that M. larici-populina under-went a soft selective sweep and possibly a prominent effect of outbreeding and recombination, which we speculate have increased the efficiency of selection.

evolutionary biology↗

bioRxiv2020

AutoNeuriteJ: An ImageJ plugin for measurement and classification of neuritic extensions

Morphometry characterization is an important procedure in describing neuronal cultures and identifying phenotypic differences. This task usually requires labor-intensive measurements and the classification of numerous neurites from large numbers of neurons in culture. To automate these measurements, we wrote AutoNeuriteJ, an imageJ/Fiji plugin that measures and classifies neurites from a very large number of neurons. We showed that AutoNeuriteJ is able to detect variations of neuritic growth induced by several compounds known to affect the neuronal growth. In these experiments measurement of more than 5000 mouse neurons per conditions was obtained within a few hours. Moreover, by analyzing mouse neurons deficient for the microtubule associated protein 6 (MAP6) and wild type neurons we illustrate that AutoNeuriteJ is capable to detect subtle phenotypic difference in axonal length. Overall the use of AutoNeuriteJ will provide rapid, unbiased and accurate measurement of neuron morphologies.

bioinformatics↗

bioRxiv2020

Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of Huntingtin

Studies have suggested that amyloid precursor protein (APP) regulates synaptic homeostasis, but the evidence has not been consistent. In particular, signaling pathways controlling APP transport to the synapse in axons and dendrites remain to be identified. Having previously shown that Huntingtin (HTT), the scaffolding protein involved in Huntingtons disease, regulates neuritic transport of APP, we used a microfluidic corticocortical neuronal network-on-a-chip to examine APP transport and localization to the pre- and post-synaptic compartments. We found that HTT, upon phosphorylation by the Ser/Thr kinase Akt, regulates APP transport in axons but not dendrites. Expression of an unphosphorylatable HTT decreased axonal anterograde transport of APP, reduced presynaptic APP levels, and increased synaptic density. Ablating in vivo HTT phosphorylation in APPPS1 mice, which overexpress APP, reduced presynaptic APP levels, restored synapse number and improved learning and memory. The Akt-HTT pathway and axonal transport of APP thus regulate APP presynaptic levels and synapse homeostasis.

neuroscience↗

bioRxiv2020

Modeling disease-correlated TUBA1A mutation in budding yeast reveals a molecular basis for tubulin dysfunction

Malformations of cortical development (MCD) of the human brain are a likely consequence of defective neuronal migration, and/or proliferation of neuronal progenitor cells, both of which are dictated in part by microtubule-dependent transport of various cargoes, including the mitotic spindle. Throughout the evolutionary spectrum, proper spindle positioning depends on cortically anchored dynein motors that exert forces on astral microtubules emanating from spindle poles. A single heterozygous amino acid change, G436R, in the conserved TUBA1A -tubulin gene was reported to account for MCD in patients. The mechanism by which this mutation disrupts microtubule function in the developing cerebral cortex is not understood. Studying the consequence of tubulin mutations in mammalian cells is challenging partly because of the large number of -tubulin isotypes expressed. To overcome this challenge, we have generated a budding yeast strain expressing the mutated tubulin (Tub1G437R in yeast) as one of the main sources of -tubulin (in addition to Tub3, another -tubulin isotype in this organism). Although viability of the yeast was unimpaired by this mutation, they became reliant on Tub3, as was apparent by the synthetic lethality of this mutant in combination with tub3{Delta}. We find that Tub1G437R assembles into microtubules that support normal G1 activity, but lead to enhanced dynein-dependent nuclear migration phenotypes during G2/M, and a consequential disruption of spindle positioning. We find that this mutation impairs the interaction between She1 - a negative regulator of dynein - and microtubules, as was apparent from a yeast two-hybrid assay, a co-sedimentation assay, and from live cell imaging. We conclude that a weaker interaction between She1 and Tub1G437R-containing microtubules results in enhanced dynein activity, ultimately leading to the spindle positioning defect. Our results provide the first evidence of an impaired interaction between microtubules and a dynein regulator as a consequence of a tubulin mutation, and sheds light on a mechanism that may be causative of neurodevelopmental diseases.

cell biology↗

bioRxiv2020

Two antagonistic microtubule targeting drugs act synergistically to kill cancer cells

Paclitaxel is a microtubule stabilizing agent and a successful drug for cancer chemotherapy inducing, however, adverse effects. To reduce the effective dose of paclitaxel, we searched for drugs which could potentiate its therapeutic effect. We have screened a chemical library and selected Carba1, a carbazolone, which exerts synergistic cytotoxic effects on tumor cells grown in vitro, when co-administrated with a low dose of paclitaxel. Carba1 targets the colchicine binding-site of tubulin and is a microtubule-destabilizing agent. The Carba1-induced modulation of microtubule dynamics increases the accumulation of fluorescent paclitaxel inside microtubules, providing a mechanistic explanation of the observed synergy between Carba1 and paclitaxel. The synergistic effect of Carba1 with paclitaxel on tumor cell viability was also observed in vivo in xenografted mice. Thus, a new mechanism favoring paclitaxel accumulation in microtubules can be transposed to in vivo mouse cancer treatments, paving the way for new therapeutic strategies combining low doses of microtubule targeting agents with opposite mechanisms of action.

cancer biology↗