Biology subjects

Michel, G.

Publications and source records attributed to Michel, G..

10 recordsLinked to original sources

bioRxiv2025

Depletion of CX3CR1+ macrophages results in disrupted functionality and immune surveillance within epididymis and testis

A finely tuned immune regulation within the epididymis and testis is essential for male reproductive health. This balance is especially critical in the epididymis, where sperm mature and ascending infections frequently disrupt homeostasis, resulting in regionally different immune responses and potential long-term fertility impairments. We previously demonstrated that the epididymis harbors a region-specific immunological scaffold, with CX3CR1+ macrophages as the most prominent epithelium-associated immune cell population. Here, we established a transgenic mouse model to selectively deplete these intraepithelial CX3CR1+ macrophages within the epididymis, resulting in focal epithelial damage and impaired sperm maturation processes essential for proper sperm functionality. Additionally, a mild reduction of the testicular macrophage pool resulted in transient disruptions in spermatogenesis and steroidogenesis. Although the macrophage niche was repopulated after depletion, the newly recruited cells displayed altered phenotypes consistent with persistent sperm alterations. Following infection with uropathogenic Escherichia coli (UPEC), macrophage-depleted mice exhibited exacerbated immune responses - particularly in normally protected proximal epididymal regions - with earlier onset and more severe tissue damage. Transcriptomic analysis revealed a failure to restrain inflammatory responses, especially in genes involved in immune regulation and antibacterial defense, accompanied by elevated immune cell infiltration in infected macrophage-depleted mice. Overall, our findings confirm a crucial role for CX3CR1 macrophages in preserving epithelial integrity and modulating immune responses, supporting a stable tissue environment necessary for efficient organ function of both epididymis and testis. Significance statementMaintaining immune balance in the epididymis is essential for tissue health and protection against ascending infections. Using a transgenic mouse model that allows for selective depletion of CX3CR1 macrophages, this study examines their role in both the epididymis and testis under normal and infectious conditions. The results show that the removal of these macrophages causes localized epithelial damage, changes in immune cell make-up, and increased inflammation in the epididymis after bacterial infection, while also causing mild, reversible problems with spermatogenesis and steroid production in the testis. These findings support the idea that CX3CR1 macrophages contribute to region-specific immune regulation and epithelial stability--key features for keeping the tissue environment suitable for proper sperm development.

immunology↗

bioRxiv2023

THE RHODOEXPLORER PLATFORM FOR RED ALGAL GENOMICS AND WHOLE GENOME ASSEMBLIES FOR SEVERAL GRACILARIA SPECIES

Macroalgal (seaweed) genomic resources are generally lacking as compared to other eukaryotic taxa, and this is particularly true in the red algae (Rhodophyta). Understanding red algal genomes is critical to understanding eukaryotic evolution given that red algal genes are spread across eukaryotic lineages from secondary endosymbiosis and red algae diverged early in the Archaeplastids. The Gracilariales are highly diverse and widely distributed order whose species can serve as ecosystem engineers in intertidal habitats, including several notorious introduced species. The genus Gracilaria is cultivated worldwide, in part for its production of agar and other bioactive compounds with downstream pharmaceutical and industrial applications. This genus is also emerging as a model for algal evolutionary ecology. Here, we report new whole genome assemblies for two species (G. chilensis and G. gracilis), a draft genome assembly of G. caudata, and genome annotation of the previously published G. vermiculophylla genome. To facilitate accessibility and comparative analysis, we integrated these data in a newly created web-based portal dedicated to red algal genomics (https://rhodoexplorer.sb-roscoff.fr). These genomes will provide a resource for understanding algal biology and, more broadly, eukaryotic evolution.

genomics↗

bioRxiv2023

Ingestion of Bacillus cereus spores dampens the immune response to favor bacterial persistence

Spores are considered as dormant entities highly resistant to extreme conditions. Among them, Bacillus cereus spores are commonly associated with foodborne outbreaks. Nevertheless, the pathological processes associated with spore ingestion and germination remain poorly understood. Here, we show that while ingestion of vegetative bacteria leads to their elimination from the midgut and small intestines of Drosophila and mice, respectively, a single ingestion of spores leads to the persistence of bacteria for at least 10 days. Using Drosophila genetics, we demonstrate that spores escape the innate immune response of the anterior midgut. Once in the posterior midgut, spores germinate, and the vegetative cells dampen the immune signaling through the induction of amidases which are negative regulators of the immune response. This study provides evidence for how B. cereus spores hijack the intestinal immune defenses allowing the localized birth of vegetative bacteria responsible for the digestive symptoms associated with foodborne illness outbreaks.

immunology↗

bioRxiv2023

Monitoring plasma nucleosome concentrations to measure of disease response and progression in dogs with hematopoietic malignancies.

BackgroundHematopoietic malignancies are extremely common in pet dogs and represent nearly 30% of the malignancies diagnosed in this population each year. Clinicians commonly use existing tools such as physical exam findings, radiographs, ultrasound and baseline blood work to monitor these patients for treatment response and remission. Circulating biomarkers, such as prostate specific antigen or carcinoembryonic antigen, can be useful tools for monitoring treatment response and remission status in human cancer patients. To date, there has a been a lack of useful circulating biomarkers available to veterinary oncology patients. MethodsCirculating plasma nucleosome concentrations were evaluated at diagnosis, throughout treatment and during remission monitoring for 40 dogs with lymphoma, acute myelogenous leukemia and multiple myeloma. Additionally, C-reactive protein and thymidine kinase-1 levels were recorded. ResultsPlasma nucleosome concentrations were significantly higher at diagnosis and progressive disease than they were when dogs were in remission. All but two dogs had plasma nucleosome concentrations that returned to the low range during treatment. These two dogs had the shortest progression free and overall survival times. Dogs with the highest plasma nucleosome concentrations had a significantly shorter first progression free survival than dogs with lower plasma nucleosome concentrations at diagnosis. Plasma nucleosome concentrations correlated better with disease response and progression than either thymidine kinase or C reactive protein. ConclusionsPlasma nucleosome concentrations can be a useful tool for treatment monitoring and disease progression in dogs with hematopoietic malignancies.

cancer biology↗

bioRxiv2022

ATM and MSH2 control blunt DNA end joining in immunoglobulin class switch recombination

Class switch recombination (CSR) produces secondary immunoglobulin isotypes and requires AID-dependent DNA deamination of intronic switch (S) regions within the immunoglobulin heavy chain (Igh) gene locus. Non-canonical repair of deaminated DNA by mismatch repair (MMR) or base excision repair (BER) creates DNA breaks that permit recombination between distal S regions. ATM-dependent phosphorylation of AID at serine-38 (pS38-AID) promotes its interaction with APE1, a BER protein, suggesting that ATM regulates CSR through BER. However, pS38-AID may also function in MMR during CSR, although the mechanism remains unknown. To examine whether ATM modulates BER- and/or MMR-dependent CSR, Atm-/- mice were bred to mice deficient for the MMR gene Msh2. Surprisingly, the predicted Mendelian frequencies of Atm-/-Msh2-/- adult mice were not obtained. To generate ATM and MSH2-deficient B cells, Atm was conditionally deleted on an Msh2-/- background using a floxed ATM allele [Atmf] and B cell-specific Cre recombinase expression (CD23-cre) to produce a deleted ATM allele (AtmD). As compared to AtmD/Dand Msh2-/- mice and B cells, AtmD/DMsh2-/- mice and B cells display a reduced CSR phenotype. Interestingly, S-S{gamma}1 junctions from AtmD/DMsh2-/-B cells that were induced to switch to IgG1 in vitro showed a significant loss of blunt end joins and an increase in insertions as compared to wildtype, AtmD/D, or Msh2-/- B cells. This data indicates that the absence of both ATM and MSH2 blocks non-homologous end joining (NHEJ), leading to inefficient CSR. We propose a model whereby ATM and MSH2 function cooperatively to regulate end-joining during CSR through pS38-AID. SummaryLoss of the DNA repair genes Atm and Msh2 produces a novel synthetic lethality in mice. B cell specific deletion of Atm on an Msh2-/- background reduces Ig CSR and inhibits NHEJ.

immunology↗

bioRxiv2022

FGF10 triggers de novo alveologenesis in a BPD model: impact on the resident mesenchymal niche cells

Bronchopulmonary dysplasia (BPD) is a neonatal lung disease developing in premature babies characterized by arrested alveologenesis and associated with decreased Fibroblast growth factor 10 (FGF10) expression. One-week hyperoxia (HYX) exposure of newborn mice leads to a permanent arrest in alveologenesis. To test the role of Fgf10 signaling to promote de novo alveologenesis following hyperoxia, we used transgenic mice allowing inducible expression of Fgf10 and recombinant FGF10 (rFGF10) protein delivered intraperitoneally. We carried out morphometry analysis, and IF on day 45. Alveolospheres assays were performed co-culturing AT2s from normoxia (NOX) with FACS-isolated Sca1Pos resident mesenchymal cells (rMC) from animals exposed to NOX, HYX+PBS, or HYX+FGF10. scRNAseq between rMC-Sca1Pos isolated from NOX and HYX+PBS were also carried out. Transgenic overexpression of Fgf10 and rFGF10 administration rescued the alveologenesis defects following HYX. Alveolosphere assays indicate that the activity of rMC-Sca1Pos is negatively impacted by HYX and partially rescued by rFGF10 treatment. Analysis by IF demonstrates a significant impact of rFGF10 on the activity of resident mesenchymal cells. scRNAseq results identified clusters expressing Fgf10, Fgf7, Pdgfra, and Axin2, which could represent the rMC niche cells for the AT2 stem cells. In conclusion, we demonstrate that rFGF10 administration is able to induce de-novo alveologenesis in a BPD mouse model and identified subpopulations of rMC-Sca1Pos niche cells potentially representing its cellular target.

cell biology↗

bioRxiv2022

Constructive Connectomics: how neuronal axons get from here to there using gene-expression maps derived from their family trees

During brain development, billions of axons must navigate over multiple spatial scales to reach specific neuronal targets, and so build the processing circuits that generate the intelligent behavior of animals. However, the limited information capacity of the zygotic genome puts a strong constraint on how, and which, axonal routes can be encoded. We propose and validate a mechanism of development that can provide an efficient encoding of this global wiring task. The key principle, confirmed through simulation, is that basic constraints on mitoses of neural stem cells--that mitotic daughters have similar gene expression to their parent and do not stray far from one another--induce a global hierarchical map of nested regions, each marked by the expression profile of its common progenitor population. Thus, a traversal of the lineal hierarchy generates a systematic sequence of expression profiles that traces a staged route, which growth cones can follow to their remote targets. We have analyzed gene expression data of developing and adult mouse brains published by the Allen Institute for Brain Science, and found them consistent with our simulations: gene expression indeed partitions the brain into a global spatial hierarchy of nested contiguous regions that is stable at least from embryonic day 11.5 to postnatal day 56. We use this experimental data to demonstrate that our axonal guidance algorithm is able to robustly extend arbors over long distances to specific targets, and that these connections result in a qualitatively plausible connectome. We conclude that, paradoxically, cell division may be the key to uniting the neurons of the brain. Author SummaryThe embryological development of each brain installs an essentially identical communication network between its cells that is roughly as complex as that between the billions of people living on Earth. Although vast scientific resources are currently applied to identifying the final pattern of connections, the connectome, there has until now been relatively little effort to answer the fundamental question of how this complex network across billions of neurons realized through the mitotic elaboration of the initial embryonic cell. The problem is sharpened by the constraints that construction of the network is limited by the information budget of the initial genome, and that it has no pre-existing address space for placing neurons and guiding axons. We explain how Biology can solve this problem by using the family tree of neurons to install a global space of molecular addresses, which axons can use to navigate from their source neuron to its relatives. We provide experimental evidence for this familial address space in gene expression patterns of the developing mouse brain, and demonstrate through simulation that the experimentally observed address space indeed supports global navigation to produce a qualitatively plausible default connectome.

neuroscience↗

bioRxiv2020

A single bacterial sulfatase is required for metabolism of colonic mucin O-glycans and intestinal colonization by a symbiotic human gut bacterium

Humans have co-evolved with a dense community of microbial symbionts that inhabit the lower intestine. In the colon, secreted mucus creates a physical barrier that separates these microbes from the intestinal epithelium. Some gut bacteria are able to utilize mucin glycoproteins, the main mucus component, as a nutrient source. However, it remains unclear which bacterial enzymes initiate the degradation of the highly complex O-glycans found in mucins. In the colon, these glycans are heavily sulfated, but the specific sulfatases that are active on colonic mucins have not been identified. Here, we show that sulfatases are essential to the utilization of colonic mucin O-glycans by the human gut symbiont Bacteroides thetaiotaomicron. We have characterized the activity of 12 different sulfatases encoded by this species, showing that these enzymes collectively are active on all of the known sulfate linkages in colonic O-glycans. Crystal structures of 3 enzymes provide mechanistic insight into the molecular basis of substrate-specificity. Unexpectedly, we found that a single sulfatase is essential for utilization of sulfated O-glycans in vitro and also plays a major role in vivo. Our results provide insight into the mechanisms of mucin degradation by gut bacteria, an important process for both normal microbial gut colonization and diseases such as inflammatory bowel disease (IBD). Sulfatase activity is likely to be a keystone step in bacterial mucin degradation and inhibition of these enzymes may therefore represent a viable therapeutic path for treatment of IBD and other diseases.

microbiology↗

bioRxiv2019

Temporal trends in incidence of childhood cancer in Switzerland, 1985-2014

STRUCTURED ABSTRACTO_ST_ABSBackgroundC_ST_ABSIncidence of childhood cancer increased in most countries worldwide, but the reasons are unclear. This study investigates trends in childhood cancer incidence in Switzerland from 1985 to 2014.\n\nMethodsWe extracted data on all childhood cancer cases diagnosed at ages 0-14 years in Switzerland from the Swiss Childhood Cancer Registry. We included ICCC-3 main groups I-XII and calculated age-standardised, cumulative, and age-specific incidence for different diagnostic groups. We analysed trends in annual age-standardised incidence using JoinPoint regression models.\n\nResultsOver the study period from 1985-2014, 5104 of 5486 cancer diagnoses (93%) were microscopically verified. The proportion of children treated in paediatric cancer centres increased from 84% during 1985-1994 to 93% in 1995-2004 and 98% in 2005-2014 (p<0.001). Using the 2010 European standard population, age-standardised incidence was 143 in 1985-1994, 154 in 1995-2004, and 162 per million in 2005-2014. Over the period 1985-2014, incidence for all cancers increased by 0.7% (95% confidence interval [CI] 0.5-1.0) per year, 0.8% (95% CI 0.2%-1.4%) for leukaemias, 3.8% (95% CI 1.7%-6.0%) for epithelial neoplasms and melanomas, and 3.0% (95% CI 1.3%-4.6%) for CNS tumours for the period 1985-2002.\n\nConclusionTrends in incidence were driven mostly by increases among leukaemias and CNS tumours. For CNS tumours, observed trends may be explained at least partially by diagnostic changes and improved registration. For leukaemias, rising incidence may be real and at least partly due to changes in risk factors.\n\nHighlightsO_LIIn Switzerland, incidence of childhood cancer increased by 18% from 1985-2014.\nC_LIO_LIIncrease in incidence was mainly caused by brain tumours and leukaemias.\nC_LIO_LIImproved registration and diagnostics may have increased brain tumour incidence.\nC_LIO_LIIncreasing trend for leukaemias may be real, but reasons remain elusive.\nC_LI

epidemiology↗

bioRxiv2018

A Gene Regulatory Model of Cortical Neurogenesis

Sparse data describing mouse cortical neurogenesis were used to derive a model gene regulatory network (GRN) that is then able to control the quantitative cellular dynamics of the observed neurogenesis. Derivation of the network begins by estimating from the biological data a set of cell states and transition probabilities necessary to explain neurogenesis. We show that the stochastic transition between states can be implemented by the dynamics of a GRN comprising only 36 abstract genes. Finally, we demonstrate using detailed physical simulations of cell mitosis, and differentiation that this GRN is able to steer a population of neuroepithelial precursors through mitotic expansion and differentiation to form the quantitatively correct complex multicellular architectures of mouse cortical areas 3 and 6. We find that the same GRN is able to generate both areas though modulation of only one gene, suggesting that arealization of the cortical sheet may require only simple improvisations on a fundamental gene network. We conclude that even sparse phenotypic and cell lineage data can be used to infer fundamental properties of neurogenesis and its organization.\n\n1. HighlightsO_LIEstimation of the cell states and transition probabilities of neurogenesis from experimental data.\nC_LIO_LIDesign of an abstract gene regulatory network (GRN) whose dynamics implement cell states and their stochastic transitions.\nC_LIO_LIDetailed simulation of GRN-guided neurogenesis for mouse cortical areas 3 and 6.\nC_LIO_LIDifferent dynamics of neurogenesis of distinct cortical areas arise through modulation of only a single gene.\nC_LI\n\n2. In briefPfister et al. show how sparse phenotypic and cell lineage data can be used to infer a small abstract gene regulatory network (GRN), which, when inserted into model precursor cells, is able to control in a distributed manner the quantitative cellular dynamics of neocortical neurogenesis.

neuroscience↗