Biology subjects

Zeuschner, D.

Publications and source records attributed to Zeuschner, D..

7 recordsLinked to original sources

bioRxiv2025

Fibroblast depletion reveals mammalian epithelial resilience across neonatal and adult stages

Regenerative organs, like the skin, depend on niche-stem cell interactions that sustain continuous cellular turnover. In cell culture, skin fibroblasts promote epidermal stem cell proliferation and differentiation. Yet, it remains elusive how fibroblasts regulate epidermal stem cell behaviors and differentiation in skin in vivo. Here, we asked how fibroblast depletion may impact epidermal stem cell proliferation in the context of adult homeostasis. Surprisingly, we find that significant depletion of fibroblast density does not affect epidermal stem cell proliferative capacity during adult stages in vivo. We next probed earlier neonatal stages when skin is actively remodeling but found no change in epidermal stem cell proliferative capacity following fibroblast depletion. These results demonstrate that across different ages, epidermal stem cell proliferative capacity can persist in the face of a largely reduced fibroblast population. Interestingly, neonatal fibroblast depletion does not significantly reduce their secreted collagen I density but affects basement membrane mechanics and epidermal stem cell delamination. Despite these changes, the skin continues to maintain its protective barrier function. Thus, our work demonstrates the skin regenerative program employs robust compensatory mechanisms in the face of fibroblast depletion to maintain functional capacity.

cell biology↗

bioRxiv2024

Alveolar macrophages initiate the spatially targeted neutrophil recruitment during nanoparticle inhalation

Exposure to air pollution, including nanoparticles (NPs), is a major health concern associated with various diseases, triggered by subtle inflammatory responses in the lung. To investigate the dynamic immune response in vivo, lung intravital microscopy (L-IVM), was used to analyze the behavior of alveolar macrophages (AMs) and neutrophils, combined with ventilator-assisted inhalation of nebulized NPs in mice. Inhalation of fluorescent quantum dot NPs (cQDs) and soot-like carbon black NPs (CNPs, ambient pollutants), led to rapid spatially focused recruitment of neutrophils near alveolar deposited NPs. Neutrophil recruitment was initiated by NPs uptake by AMs, dependent on AM motility and AM NP surface recognition. Prior airway application of neutralizing antibodies against alveolar ICAM-1 and LFA-1, leading to reduced AM motility, inhibition of C5aR1 and Fc{gamma}RI receptor mediated NPs uptake by AMs, as well as neutralizing of TNF and application of a cellular degranulation inhibitor, abolished the early immune response induced by NPs. Overall, our data demonstrates the crucial role of AM activity (migration, phagocytosis, cytokine release) in the rapid and site-specific recruitment of neutrophils during the early phase of particle inhalation, suggesting these processes to be key events in mounting the immune response upon NP inhalation in the lung. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=175 HEIGHT=200 SRC="FIGDIR/small/623349v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@d67e38org.highwire.dtl.DTLVardef@1f8c139org.highwire.dtl.DTLVardef@55be9dorg.highwire.dtl.DTLVardef@1555042_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

FUS controls muscle differentiation and structure through LLPS mediated recruitment of MEF2 and ETV5

FUS is an RNA binding protein mutated in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive muscle weakness. We show that ALS-associated FUS mutations lead to ultrastructural defects in muscle of FUS-ALS patients, with disruption of sarcomeres and mitochondria. Studies in mouse and Drosophila models demonstrate an evolutionary-conserved cell autonomous function of FUS in muscle development. Mechanistically, FUS is required for transcription of MEF2 dependent genes, binds to the promoter of genes bound by ETS transcription factors in particular ETV5 and co-activates transcription of MEF2 dependent genes with ETV5. FUS phase separates with ETV5 and MEF2A, and MEF2A binding to FUS is potentiated by ETV5. Last, Etv5 haploinsufficiency exacerbates muscle weakness in a mouse model of FUS-ALS. These findings establish FUS as an essential protein for skeletal muscle structure through its phase separation-dependent recruitment of ETV5 and MEF2, defining a novel pathway compromised in FUS-ALS.

neuroscience↗

bioRxiv2024

In vitro spatiotemporal reconstruction of human skeletal muscle organogenesis

Spatiotemporal recapitulation of long-range trajectories for lineages that influence body patterning along the medio-lateral and proximal-distal axes during embryogenesis in an in vitro system remains elusive. Here we introduce a three-dimensional organoid approach, termed Gastruloids-Lateraloid-Musculoids (GLMs), to model human neural crest, lateral plate mesoderm and skeletal muscle lineage development at the forelimb level following gastrulation and during limb patterning. GLMs harvest neuro-mesodermal progenitors with the potential to establish neural and paraxial mesodermal populations, while single cell analyses and spatial transcriptomics demonstrate promotion of mesodermal lineage segregation during gastrulation and spatial recapitulation of migration events along the medio-lateral axis for vagal neural crest, hypaxial myogenesis and lateral plate mesodermal lineages. Comparative analyses to developmental atlases and adult muscle stem cell data confirm a pool of hypaxial migrating myogenic progenitors that in a niche dependent manner change their embryonic anatomical developmental program to a fetal myogenic program, thus enabling them to resist specification in a cell autonomous manner and facilitate long term in vitro expansion. GLMs model human myogenesis at the forelimb level, establish fetal muscle stem cells equivalent to those that sustain the growth phase of the embryo and provide a 3D in vitro system for investigating neural crest, early fore-gut and lateral plate mesoderm development.

developmental biology↗

bioRxiv2023

Spatial organization and function of RNA molecules within phase-separatedcondensates are controlled by Dnd1

Germ granules, condensates of phase-separated RNA and protein, are organelles essential for germline development in different organisms The patterning of the granules and its relevance for germ cell fate are not fully understood. Combining three-dimensional in vivo structural and functional analyses, we study the dynamic spatial organization of molecules within zebrafish germ granules. We find that localization of RNA molecules to the periphery of the granules, where ribosomes are localized depends on translational activity at this location. In addition, we find that the vertebrate-specific Dead end (Dnd1) protein is essential for nanos3 RNA localization at the condensates periphery. Accordingly, in the absence of Dnd1, or when translation is inhibited, nanos3 RNA translocates into the granule interior, away from the ribosomes, a process that is correlated with loss of germ cell fate. These findings highlight the relevance of sub-granule compartmentalization for posttranscriptional control, and its importance for preserving germ cell totipotency.

cell biology↗

bioRxiv2023

Glial-dependent clustering of voltage-gated ion channels in Drosophila precedes myelin formation

Neuronal information conductance depends on transmission of action potentials. The conductance of action potentials is based on three physical parameters: The axial resistance of the axon, the axonal insulation by glial membranes, and the positioning of voltage-gated ion channels. In vertebrates, myelin and channel clustering allow fast saltatory conductance. Here we show that in Drosophila melanogaster voltage-gated sodium and potassium channels, Para and Shal, co-localize and cluster in an area of motor axons resembling the axon initial segment. Para but not Shal localization depends on peripheral glia. In larvae, relatively low levels of Para channels are needed to allow proper signal transduction and nerves are simply wrapped by glial cells. In adults, the concentration of Para at the axon initial segment increases. Concomitantly, these axon domains are covered by a mesh of glial processes forming a lacunar structure that serves as an ion reservoir. Directly flanking the voltage-gated ion channel rich axon segment, the lacunar structures collapse forming a myelin-like insulation. Thus, Drosophila development may reflect the evolution of myelin which forms in response to increased levels of clustered voltage-gated ion channels. One-Sentence SummaryEvolution of saltatory conductance is mirrored in fly development where glia dependent clustering of voltage-gated ion channels precedes myelination.

neuroscience↗

bioRxiv2022

Early endosomes act as local exocytosis hubs to repair endothelial membrane damage

The plasma membrane of a cell is subject to stresses causing ruptures that must be repaired immediately to preserve membrane integrity and ensure cell survival. Yet, the spatio-temporal membrane dynamics at the wound site and the source of membrane required for wound repair are poorly understood. Here, we show that early endosomes, previously only known to function in the uptake of extracellular material and its endocytic transport, are involved in plasma membrane repair in human endothelial cells. Using live-cell imaging and correlative light and electron microscopy, we demonstrate that membrane injury triggers a previously unknown exocytosis of early endosomes that is induced by Ca2+ entering through the wound. This exocytosis is restricted to the vicinity of the wound site and mediated by the endosomal SNARE VAMP2, which is crucial for efficient membrane repair. Thus, the here identified Ca2+-evoked and localized exocytosis of early endosomes supplies the membrane material required for rapid resealing of a damaged plasma membrane, thereby providing the first line of defense against damage in mechanically challenged endothelial cells.

cell biology↗