Biology subjects

Peron, S.

Publications and source records attributed to Peron, S..

10 recordsLinked to original sources

bioRxiv2026

Cell cycle exit is required for differentiation and cell fate diversification but not neoblast specialisation in planarians

In planarians, adult stem cells constantly proliferate and differentiate into dozens of different cell types to maintain tissue homeostasis. However, how cell fate acquisition is coordinated with cell cycle progression remains poorly understood. To address this, we generated single-cell RNA-sequencing datasets from cells enriched for 2C or 4C DNA content and from animals subjected to RNAi against the cell cycle regulators cdh1 and h2b. We found that progenitor populations from multiple lineages contain actively cycling cells enriched in the 4C state. Cell fate acquisition to most cell types is acquired progressively during neoblast differentiation. Comparative analysis of cell cycle regulators confirmed a simplified regulatory repertoire in Schmidtea, supporting a central role for cdh1 in controlling cell cycle exit. RNAi-mediated knockdown of cdh1 caused homeostasis defects, impaired regeneration, accumulation of neoblasts and depletion of progenitors. Together, our findings demonstrate that cell cycle exit is required for terminal differentiation but not for neoblast specialisation. Instead, lineage commitment is initiated in actively cycling neoblasts, whereas terminal differentiation depends on cdh1-mediated cell cycle exit.

systems biology↗

bioRxiv2025

Staphylococcus aureus derived extracellular vesicles trigger multiple inflammatory pathways in host cells and deliver their RNA cargo following their internalization and lysis within late endosomes

Staphylococcus aureus is a major opportunistic Gram-positive pathogen whose virulence can be partly mediated by extracellular vesicles (EVs). These nanosized particles carry a diverse cargo and can play key roles in host-pathogen interactions. Here, we investigated the production, composition, and host cell interactions of EVs secreted by the methicillin-resistant S. aureus strain N315, one of the most widely studied clinical isolates. To mimic infection, EVs produced from RPMI supplemented with 10% LB were purified by size exclusion chromatography, and characterized by nanoparticle tracking analysis and electron microscopy. N315 EVs contained a diverse molecular cargo, selectively enriched, and including proteins, lipoproteins, DNA, RNA, lipoteichoic acid, and peptidoglycan. Protection assays and confocal microscopy confirmed the intravesicular localization of RNAs and proteins. N315 EVs were recognized by multiple host pattern recognition receptors (PPRs) in human MG-63 cells, located at the cell surface (TLR1, TLR2, TLR4, TLR6), within endosomes (TLR3, TLR7, TLR4) and in the cytoplasm (NOD2). EV exposure promoted the selective upregulation of these PRRs, activated the NF-{kappa}B and JAK/STAT signaling pathways, and induced the expression of pro-inflammatory cytokines such as IL1{beta}, IL6, and CXCL8. N315 EVs were internalized via a dynamin-dependent endocytosis mechanism and trafficked to late endosomes, where RNA cargo release occurred. Importantly, inhibition of EVs uptake altered cytokine gene expression, confirming that internalization is required for immunomodulation. This work provides a better understanding of the mechanisms of interaction of S. aureus EVs with host cells and sheds light on the fate of EVs and their cargo once internalized by cells. IMPORTANCEAntibiotic resistance, coupled with the limited discovery of new antimicrobial agents, poses a growing threat to public health. Staphylococcus aureus is one of the six highly virulent and antibiotic-resistant bacterial species responsible for both severe hospital- and community-acquired infections. This pathogen demonstrates a remarkable ability to adapt to diverse hosts and environments and to produce a broad arsenal of virulence factors. Gaining deeper insight into its pathogenic mechanisms and host interactions may reveal novel therapeutic targets and alternative treatment strategies. Over the past decade, a key advancement has been the identification of extracellular vesicle production by S. aureus and its critical role as a new secretion system for virulence factors. This study shed light on the immunogenic effect of EVs and their role as a vehicle for the delivery of their contents into host cells. These adjuvant-like properties open new avenues for research and potential intervention.

microbiology↗

bioRxiv2023

Reprogramming early cortical astroglia into neurons with hallmarks of fast-spiking parvalbumin-positive interneurons by phospho-site deficient Ascl1

Cellular reprogramming of mammalian glia to an induced neuronal fate holds potential for restoring diseased brain circuits. While the proneural factor Ascl1 is widely used for neuronal reprogramming, in the early postnatal mouse cortex Ascl1 fails to induce glia-to-neuron conversion, instead promoting proliferation of oligodendrocyte progenitor cells (OPC). Since Ascl1 activity is post-translationally regulated, here we investigated the consequences of mutating six serine phospho-acceptor sites to alanine (Ascl1SA6) on lineage reprogramming in vivo. Ascl1SA6 exhibited increased neurogenic activity in glia of the early postnatal mouse cortex, an effect enhanced by co-expression of Bcl2. Genetic fate-mapping revealed that most induced neurons originated from astrocytes while only a few derived from OPCs. Intriguingly, many Ascl1SA6/Bcl2-induced neurons expressed parvalbumin and were capable of high-frequency action potential firing. Our study demonstrates authentic conversion of astroglia into neurons featuring subclass hallmarks of cortical interneurons, advancing our scope of engineering neuronal fates in the brain.

neuroscience↗

bioRxiv2022

Low-efficiency conversion of proliferative glia into induced neurons by Ascl1 in the postnatal mouse cerebral cortex in vivo

The proneural transcription factor Achaete-scute complex-like 1 (Ascl1) is a major regulator of neural progenitor fate, implicated both in neurogenesis and oligodendrogliogenesis. Ascl1 has been widely used to reprogram non-neuronal cells into induced neurons. In vitro, Ascl1 induces efficient reprogramming of proliferative astroglia from the early postnatal cerebral cortex into interneuron-like cells. Here, we examined whether Ascl1 can similarly induce neuronal reprogramming of glia undergoing proliferation in the postnatal mouse cerebral cortex in vivo. Toward this, we targeted cortical glia at the peak of proliferative expansion (i.e., postnatal day 5) by injecting a retrovirus encoding for Ascl1 into the mouse cerebral cortex. In sharp contrast to the very efficient reprogramming in vitro, Ascl1-transduced glial cells were converted into doublecortin-immunoreactive neurons only with low efficiency in vivo. Interfering with the phosphorylation of Ascl1 by mutation of six conserved proline-directed serine/threonine phosphorylation sites (Ascl1SA6) has been previously shown to increase its neurogenic activity in the early embryonic cerebral cortex. We therefore tested whether transduction of proliferative glia with a retrovirus encoding Ascl1SA6 improved their conversion into neurons. While in vitro glia-to-neuron conversion was markedly enhanced, in vivo reprogramming efficiency remained low. However, both wild-type and mutant Ascl1 reduced the relative number of cells expressing the astrocytic marker glial fibrillary acidic protein (GFAP) and increased the relative number of cells expressing the oligodendroglial marker Sox10 in vivo. Together, our results indicate that the enhanced neurogenic response of proliferative postnatal glia to Ascl1SA6 versus Ascl1 observed in vitro is not recapitulated in vivo.

neuroscience↗

bioRxiv2022

Increased frequencies of IgH locus suicide recombination points on Chronic Lymphocytic Leukemia with low rate of AID related somatic mutations, cMYC overexpression and short telomeres

In normal activated B-cells, Activation Induced-cytidine deaminase (AID) is absolutely required for immunoglobulin (Ig) class switch recombination (CSR) and IGHV somatic hypermutation (SHM). AID is also implicated in the Locus Suicide Recombination (LSR) of the Ig heavy (IgH) locus, resulting in the deletion of the IgH constant part. Chronic lymphocytic leukemia (CLL) is an indolent non-Hodgkin B-cell lymphoma characterized by tumor CLL B-cells that weakly express a B cell receptor (BCR) on their surface. The great majority of CLL tumor B-cells are non class-switched. Searching for abnormalities of IgH locus recombination in CLL, we investigated CSR and LSR in samples from CLL patients (N=47) with high blood tumor cell infiltration (>98%) and in healthy volunteers (HV) as controls (N=9). LSR was detectable at comparable levels in both HV and CLL groups. CSR counts were decreased in CLL samples as expected. As distribution of LSR counts was bimodal, we separated CLL patients in two groups so called LSRHigh and LSRLow. LSRHigh CLLs exhibited very weak AID expression and low mutation rate of IgHV region and of the AID off-target PIM1 gene. LSR junction diversity, evaluated using the Shannon index, was increased in LSRHigh CLLs suggesting that LSR was on-going in these cells. Also, shorter telomeres were observed in LSRHigh CLLs suggesting an increased number of past mitosis. Consistently, increased levels of cMYC expression were detected in LSRHigh CLLs and treatment free survival of these cases was markedly decreased. We hypothesized that LSR in LSRHigh CLLs is AID independent and could be due to DNA lesion and inaccurate DSB repair within the IgH locus, which could be accessible to recombination machinery due to increased IgH locus transcription. Altogether, our results indicate the accessibility of IgH locus and the proliferation increase LSR rate in LSRHigh CLLs could be related to cMYC resulting in shorter treatment free survival of patients and point on an AID independent mechanism of IgH recombination.

cancer biology↗

bioRxiv2022

Role of Yap1 in adult neural stem cell activation

Most adult hippocampal neural stem cells (NSCs) remain quiescent with only a minor portion undergoing active proliferation and neurogenesis. The molecular mechanisms that trigger eventually the transition from quiescence to activation are still poorly understood. Here, we found the activity of the transcriptional activator Yap1 to be enriched in active NSCs. Genetic deletion of Yap1 led to a significant reduction in the relative proportion of active NSCs supporting a physiological role of Yap1 in regulating the transition from quiescence to activation. Overexpression of wild type Yap1 in adult NSCs did not induce NSC activation suggesting tight upstream control mechanisms, but overexpression of a gain-of-function mutant (Yap1-5SA) elicited cell cycle entry in NSCs and hilar astrocytes. Consistent with a role of Yap1 in NSC activation, single cell RNA sequencing revealed the partial induction of an activated NSC gene expression program. Yet, Yap1-5SA expression also induced Taz and other key components of the Yap/Taz regulon previously identified in glioblastoma stem cell-like cells. Consequently, dysregulated Yap1 activity led to repression of hippocampal neurogenesis, promoting aberrant differentiation instead.

neuroscience↗

bioRxiv2019

Pattern regulation in a regenerating jellyfish

Clytia hemisphaerica jellyfish, with their tetraradial symmetry, offer a novel paradigm for addressing patterning mechanisms during regeneration. Here we show that an interplay between mechanical forces, cell migration and proliferation allows jellyfish fragments to regain shape and functionality rapidly, notably by efficient restoration of the central feeding organ (manubrium). Fragmentation first triggers actomyosin-powered remodeling that restores body umbrella shape, causing radial smooth muscle fibers to converge around "hubs" which serve as positional landmarks. Stabilization of these hubs, and associated expression of Wnt6, depends on the configuration of the adjoining muscle fiber "spokes". Stabilized hubs presage the site of the manubrium blastema, whose growth is Wnt/{beta}-catenin dependent and fueled by both cell proliferation and long-range cell recruitment. Manubrium morphogenesis is modulated by its connections with the gastrovascular canal system. We conclude that body patterning in regenerating jellyfish emerges mainly from local interactions, triggered and directed by the remodeling process.

developmental biology↗

bioRxiv2019

An improved whole life cycle culture protocol for the hydrozoan genetic model Clytia hemisphaerica.

The jellyfish species Clytia hemisphaerica (Cnidaria, Hydrozoa) has emerged as a new experimental model animal in the last decade. Favorable characters include a fully transparent body suitable for microscopy, daily gamete production and a relatively short life cycle. Furthermore, whole genome sequence assembly and efficient gene editing techniques using CRISPR/Cas9 have opened new possibilities for genetic studies. The quasi-immortal vegetatively-growing polyp colony stage provides a practical means to maintain mutant strains. In the context of developing Clytia as a genetic model, we report here an improved whole life cycle culture method including an aquarium tank system designed for culture of the tiny jellyfish form. We have compared different feeding regimes using Artemia larvae as the food and demonstrate that the stage-dependent feeding control is the key for rapid and reliable medusa and polyp rearing. Metamorphosis of the planula larvae into a polyp colony can be efficiently induced using a new synthetic peptide. The optimized procedures detailed here make it practical to generate new genetically modified Clytia strains and to safely maintain their whole life cycle in the laboratory.

developmental biology↗

bioRxiv2018

The genome of the jellyfish Clytia hemisphaerica and the evolution of the cnidarian life-cycle

Jellyfish (medusae) are a distinctive life-cycle stage of medusozoan cnidarians. They are major marine predators, with integrated neurosensory, muscular and organ systems. The genetic foundations of this complex form are largely unknown. We report the draft genome of the hydrozoan jellyfish Clytia hemisphaerica and use multiple transcriptomes to determine gene use across life-cycle stages. Medusa, planula larva and polyp are each characterised by distinct transcriptome signatures reflecting abrupt life cycle transitions, and all deploy a mixture of phylogenetically old and new genes. Medusa specific transcription factors, including many with bilaterian orthologs, associate with diverse neurosensory structures. Compared to Clytia, the polyp-only hydrozoan Hydra has lost many of the medusa-expressed transcription factors, despite similar overall rates of gene content and sequence evolution. Absence of expression and gene loss among Clytia orthologs of genes patterning the anthozoan aboral pole, secondary axis and endomesoderm support simplification of planulae and polyps in Hydrozoa, including loss of bilateral symmetry. Consequently, although the polyp and planula are generally considered the ancestral cnidarian forms, in Clytia the medusa maximally deploys ancestral cnidarian-bilaterian transcription factor gene complexity.

evolutionary biology↗

bioRxiv2017

Programming of neural progenitors of the adult subependymal zone towards a glutamatergic identity by neurogenin2

While the adult subependymal zone (SEZ) harbors pools of distinct neural stem cells that generate different types of GABAergic interneurons, a small progenitor population in the dorsal SEZ expresses Neurog2 and gives rise to glutamatergic neurons. Here we investigated whether SEZ progenitors can be programmed towards glutamatergic neurogenesis through forced expression of Neurog2. Retrovirus-mediated expression of Neurog2 induced the glutamatergic neuron lineage markers Tbr2 and Tbr1 in cultured SEZ progenitors which subsequently differentiated into functional glutamatergic neurons. Likewise, retrovirus-mediated expression of Neurog2 in dividing SEZ progenitors within the adult SEZ induced Tbr2 and Tbr1 expression, hallmarking entry into the glutamatergic lineage also in vivo. Intriguingly, Neurog2-expressing progenitors failed to enter the rostral migratory stream (RMS) and instead differentiated directly within the SEZ or the adjacent striatum. In sharp contrast, lentivirus-mediated postmitotic expression of Neurog2 failed to reprogram early SEZ neurons, which instead maintained their GABAergic identity and migrated along the RMS towards the olfactory bulb. Thus, our data show that Neurog2 can program SEZ progenitors towards a glutamatergic identity, but fails to reprogram their postmitotic progeny.\n\nSummary statementOur study identifies a critical developmental time window during which progenitors of the adult subependymal zone, specified for generating GABAergic neurons, can be reprogrammed towards glutamatergic neurogenesis.

neuroscience↗