Biology subjects

Leclerc, S.

Publications and source records attributed to Leclerc, S..

5 recordsLinked to original sources

bioRxiv2023

Astroglial Hmgb1 regulates postnatal astrocyte morphogenesis and cerebrovascular maturation.

Astrocytes are intimately linked with brain vessels, a relationship that is critical for neuronal health and function. However, astroglial factors driving these physical and functional associations during postnatal brain development have yet to be identified. We characterized structural and transcriptional changes in mouse cortical astrocytes and microvessels during the first two postnatal weeks and found that high-mobility group box 1 (Hmgb1), normally upregulated with injury and involved in adult cerebrovascular repair, was highly expressed in astrocytes at birth and then decreased rapidly. Astrocyte-selective ablation of Hmgb1 at birth affected astrocyte morphology and endfoot placement, altered distribution of endfoot proteins connexin43 and aquaporin-4, induced transcriptional changes in astrocytes related to cytoskeleton remodeling, and profoundly disrupted endothelial ultrastructure. While lack of astroglial Hmgb1 did not affect the blood-brain barrier or angiogenesis postnatally, it impaired neurovascular coupling and behavior in adult mice. These findings identify astroglial Hmgb1 as a key player in postnatal gliovascular maturation.

developmental biology↗

bioRxiv2022

Developmental role of macrophages modelled in human pluripotent stem cell derived intestinal tissue

Macrophages populate the embryo early in gestation but their role in the developmental process remains largely unknown. In particular, specification and function of macrophages in intestinal development remain unexplored. To study this event in human developmental context, we derived and combined human intestinal organoid and macrophages from pluripotent stem cells. Macrophages migrated into the organoid, proliferated, and occupied the emerging micro-anatomical niches of epithelial crypts and ganglia. They also acquired a similar transcriptomic profile to fetal intestinal macrophages and displayed tissue macrophage behaviors, such as recruitment to tissue injury. Using this model, we show that macrophages reduce glycolysis in mesenchymal cells and limit tissue growth without affecting tissue architecture, in contrast to the pro-growth effect of enteric neurons. In short, we engineered an intestinal tissue model populated with macrophages, and we suggest that resident macrophages contribute to regulation of metabolism and growth of the developing intestine.

developmental biology↗

bioRxiv2022

Enhancing adult neuroplasticity by epigenetic regulation of Parvalbumin-expressing GABAergic cells

Failure of inhibiting fear in response to harmless stimuli contributes to anxiety disorders. Extinction training only temporarily suppresses fear memories in adults, but it is highly effective in juveniles. GABAergic parvalbumin-positive (PV+) cells restrict plasticity in adult brains, thus increasing PV+ cell plasticity could promote the suppression of fear memories following extinction training in adults. Histone deacetylase 2 (Hdac2) restrains both structural and functional synaptic plasticity; however, whether and how Hdac2 controls adult PV+ cell plasticity is unknown. Here, we report that Hdac2 deletion or pharmacological inhibition in PV+ cells attenuate spontaneous recovery of fear memory after fear extinction learning in adults. These manipulations promote a temporally restricted downregulation of Acan, a critical perineuronal net component expressed exclusively by PV+ cells in medial prefrontal cortex. Finally, we show that Acan transient downregulation before extinction training but after fear memory acquisition is sufficient to reduce spontaneous fear memory recovery in wild-type mice.

neuroscience↗

bioRxiv2022

Clearance of defective muscle stem cells by senolytics reduces the expression of senescence-associated secretory phenotype and restores myogenesis in myotonic dystrophy type 1.

Muscle weakness and atrophy are clinical hallmarks of myotonic dystrophy type 1 (DM1). Muscle stem cells, which contribute to skeletal muscle growth and repair, are also affected in this disease. However, the molecular mechanisms leading to this defective activity and the impact on the disease severity are still elusive. Here, we explored through an unbiased approach the molecular signature leading to myogenic cell defects in DM1. Single cell RNAseq data revealed the presence of a specific subset of DM1 myogenic cells expressing a senescence signature, characterized by the high expression of genes related to senescence-associated secretory phenotype (SASP). This profile was confirmed using different senescence markers in vitro and in situ. Accumulation of intranuclear RNA foci in senescent cells, suggest that RNA-mediated toxicity contribute to senescence induction. High expression of IL-6, a prominent SASP cytokine, in the serum of DM1 patients was identified as a biomarker correlating with muscle weakness and functional capacity limitations. Drug screening revealed that the BCL-XL inhibitor (A1155463), a senolytic drug, can specifically target senescent DM1 myoblasts to induce their apoptosis and reduce their SASP. Removal of senescent cells re-established the myogenic function of the non-senescent DM1 myoblasts, which displayed improved proliferation and differentiation capacity in vitro; and enhanced engraftment following transplantation in vivo. Altogether this study presents a well-defined senescent molecular signature in DM1 untangling part of the pathological mechanisms observed in the disease; additionally, we demonstrate the therapeutic potential of targeting these defective cells with senolytics to restore myogenesis.

cell biology↗

bioRxiv2022

Parvovirus infection alters the nucleolar structure

The nucleolus is a biomolecular condensate essential for ribosome biogenesis and cellular stress response, and it is a key target for many DNA viruses. However, little is known about how autonomous parvovirus infection impacts nucleolar structure and function. Here, we used advanced imaging techniques, including ten-fold robust expansion microscopy (TREx), cryo soft X-ray tomography (Cryo-SXT), and interactomics and biochemical approaches, to study nucleolar remodeling during canine parvovirus infection. Infection led to redistribution of nucleolar upstream binding transcription factor 1 (inner core), fibrillarin (middle layer), and Ki-67 (outer rim). In contrast, peripheral nucleolar proteins (nucleolin and nucleophosmin) and precursor ribosomal RNAs (pre-rRNAs) remain in circularized structures. TREx and Cryo-SXT microscopy revealed profound nucleolar structural changes, including thickened perinucleolar chromatin and enlarged nucleolar low-protein density channels. BioID identified interactions between viral NS2 and nucleolar proteins in ribosome biogenesis. Northern blotting demonstrated a slowdown in ribosome biogenesis during infection. Collectively, these findings provide novel insights into how parvoviruses remodel nucleolar structure and function.

cell biology↗