Biology subjects

Wehner, D.

Publications and source records attributed to Wehner, D..

8 recordsLinked to original sources

bioRxiv2026

Genetically interacting mutations and mechanical stress affect the stochasticity of developmental eye defects in yap1 mutants

Congenital abnormalities of eye formation show remarkably variable penetrance with phenotypes even varying between left and right eyes. Here we explore this phenomenon through analysis of the mechanistic basis of low penetrance retinal coloboma in zebrafish yap1nl13/nl13 mutants and identification of factors that modify the probability of this phenotype. We find that the low penetrance stochastically occurring coloboma in yap1nl13/nl13 mutants is due to rupture in the ventral retina at the point of apposition of the lips of the closing choroid fissure and that provision of wild-type Yap in the retinal pigment epithelium suppressed this phenotype. Decreasing actomyosin contractility increased the penetrance of coloboma whereas increasing myosin phosphorylation rescued the phenotype suggesting that altered mechanical properties of the RPE sensitize the eye to stochastic failure of choroid fissure closure. Genetic interaction screening revealed enhanced and synthetic eye phenotypes in yap1nl13/nl13mutants upon abrogation of function of genes encoding extracellular matrix and other genes implicated in eye formation. Our data reveal that the variable penetrance of congenital eye abnormalities can be due to genetic and environmental factors impacting the stochastic variability inherent in the developmental processes underlying eye morphogenesis.

developmental biology↗

bioRxiv2026

In silico model of neuronal pathfinding during spinal cord regeneration in zebrafish larvae

Functional spinal cord repair in zebrafish is governed by regeneration-favorable biochemical and mechanical cues within the lesion microenvironment. Alterations in extracellular matrix composition and stiffness are closely associated with axon regeneration. However, experimentally dissecting the interplay between mechanical signals and axonal regrowth in vivo remains technically challenging. Here, we present an agent-based modeling framework to simulate stiffness-mediated axonal growth trajectories across the lesion. We use this model to explore potential mechanisms underlying the characteristic growth patterns observed during zebrafish spinal cord regeneration. Computational predictions were qualitatively compared with confocal imaging data obtained from larval zebrafish. These phenomenological comparisons revealed a close agreement between simulated and experimentally observed axon growth, indicating that experimentally observed patterns could be governed by transient changes in the stiffness profile of the spinal cord and lesion microenvironment. Hence, our computational framework provides an in silico platform for investigating the role of mechanical cues in axon regeneration in the injured spinal cord.

biophysics↗

bioRxiv2026

Reconstructing their genomes confirms the historically attested genealogy of the two medieval emperors Otto I (the Great) and Heinrich II (Saint Henry)

The Medieval Ottonian dynasty had a lasting impact on European history. We obtained ancient genomic DNA from the purported remains of Otto I (912-973) and Heinrich (Henry) II (973-1024), the first and last emperors of this dynasty, preserved in the cathedrals of Magdeburg and Bamberg, respectively. Historical records attest that they were related as a great-uncle and a grandnephew via the paternal line. Whole-genome sequencing confirms such a relationship between the two individuals, as we identify a third-degree genetic relationship based on shared DNA segments and infer matching Y haplogroups. This genetic relatedness effectively identifies the remains of the two emperors. The authentication yields a valuable resource for refining and calibrating bio-archaeological methods. Because historical records provide the precise lifespans and dates of death of these individuals, their remains can serve as a "ground-truth" for methods such as radiocarbon dating and age-at-death estimates. They can provide calibration data to improve our understanding of the radiocarbon reservoir effects of Medieval elites. As the Ottonian lineage was closely linked to the mating networks of elites across Europe, the genomes of the two emperors are valuable resources for identifying other potential elite burials.

genetics↗

bioRxiv2025

Biphasic inflammation control by dedifferentiated fibroblasts enables axon regeneration after spinal cord injury in zebrafish

Fibrosis and persistent inflammation are interconnected processes that inhibit axon regeneration in the mammalian central nervous system (CNS). In zebrafish, by contrast, fibroblast-derived extracellular matrix deposition and inflammation facilitate regeneration. However, the regulatory cross-talk between fibroblasts and the innate immune system in the regenerating CNS is not understood. Here, we show that zebrafish fibroblasts possess a dual role in inducing and subsequently resolving inflammation, which are both essential for regeneration. We identify a transient, injury-specific cthrc1a+ fibroblast state with an inflammation-associated, less differentiated, and non-fibrotic profile. Induction of this fibroblast state precedes and contributes to the initiation of the inflammatory response. At the peak of neutrophil influx, cthrc1a+ fibroblasts coordinate the resolution of inflammation. Disruption of these inflammation dynamics inhibits axon regeneration and alters the mechano-structural properties of the lesion environment. This establishes the biphasic inflammation control by dedifferentiated fibroblasts as a pivotal mechanism for CNS regeneration. ONE SENTENCE SUMMARYDedifferentiated fibroblasts sequentially induce and resolve neutrophil-driven inflammation through cytokine release to facilitate axon regeneration after spinal cord injury in zebrafish. HIGHLIGHTSO_LITime-resolved single-cell transcriptomics of zebrafish spinal cord regeneration. C_LIO_LISpinal cord injury induces fibroblast dedifferentiation. C_LIO_LIDedifferentiated fibroblasts sequentially induce and resolve inflammation. C_LIO_LIDysregulation of inflammation dynamics alters mechano-structural tissue properties. C_LI

neuroscience↗

bioRxiv2024

Wound closure after brain injury relies on force generation by microglia in zebrafish

Wound closure after a brain injury is critical for tissue restoration but this process is still not well characterised at the tissue level. We use live observation of wound closure in larval zebrafish after inflicting a stab wound to the brain. We demonstrate that the wound closes in the first 24 hours after injury by global tissue contraction. Microglia accumulation at the point of tissue convergence precedes wound closure and computational modelling of this process indicates that physical traction by microglia could lead to wound closure. Indeed, genetically or pharmacologically depleting microglia leads to defective tissue repair. Live observations indicate centripetal deformation of astrocytic processes contacted by migrating microglia. Severing such contacts leads to retraction of cellular processes, indicating tension. Weakening tension by disrupting the F-actin stabilising gene lcp1 in microglial cells, leads to failure of wound closure. Therefore, we propose a previously unidentified mechanism of brain repair in which microglia has an essential role in contracting spared tissue. Understanding the mechanical role of microglia will support advances in traumatic brain injury therapies Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=191 HEIGHT=200 SRC="FIGDIR/small/597300v3_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@112aorg.highwire.dtl.DTLVardef@6712c4org.highwire.dtl.DTLVardef@101179borg.highwire.dtl.DTLVardef@b4ecb6_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Estimation of the mass density of biological matter from refractive index measurements

The quantification of physical properties of biological matter gives rise to novel ways of understanding functional mechanisms by utilizing models that explicitly depend on physical observables. One of the basic biophysical properties is the mass density (MD), which determines the degree of crowdedness. It impacts the dynamics in sub-cellular compartments and further plays a major role in defining the opto-acoustical properties of cells and tissues. As such, the MD can be connected to the refractive index (RI) via the well known Lorentz-Lorenz relation, which takes into account the polarizability of matter. However, computing the MD based on RI measurements poses a challenge as it requires detailed knowledge of the biochemical composition of the sample. Here we propose a methodology on how to account for a priori and a posteriori assumptions about the biochemical composition of the sample as well as respective RI measurements. To that aim, we employ the Biot mixing rule of RIs alongside the assumption of volume additivity to find an approximate relation of MD and RI. We use Monte-Carlo simulations as well as Gaussian propagation of uncertainty to obtain approximate analytical solutions for the respective uncertainties of MD and RI. We validate this approach by applying it to a set of well characterized complex mixtures given by bovine milk and intralipid emulsion. Further, we employ it to estimate the mass density of trunk tissue of living zebrafish (Danio rerio) larvae. Our results enable quantifying changes of mass density estimates based on variations in the a priori assumptions. This illustrates the importance of implementing this methodology not only for MD estimations but for many other related biophysical problems, such as mechanical measurements using Brillouin microscopy and transient optical coherence elastography.

biophysics↗

bioRxiv2022

Small leucine-rich proteoglycans inhibit CNS regeneration by modifying the structural and mechanical properties of the lesion environment

Extracellular matrix (ECM) deposition after central nervous system (CNS) injury leads to inhibitory scarring in mammals, whereas it facilitates axon regeneration in the zebrafish. However, the molecular basis of these different fates is not understood. Here, we identify small leucine-rich proteoglycans (SLRPs) as a causal factor in regeneration failure. We demonstrate that the SLRPs Chondroadherin, Fibromodulin, Lumican, and Prolargin are enriched in human, but not zebrafish, CNS lesions. Targeting SLRPs to the zebrafish injury ECM inhibits axon regeneration and functional recovery. Mechanistically, we find that SLRPs confer structural and mechanical properties to the lesion environment that are adverse to axon growth. Our study reveals SLRPs as previously unknown inhibitory ECM factors in the human CNS that impair axon regeneration by modifying tissue mechanics and structure. ONE SENTENCE SUMMARYComposition, structural organization, and mechanical properties of the injury ECM direct central nervous system regeneration.

neuroscience↗

bioRxiv2018

Dynamic control of proinflammatory cytokines Il-1β and Tnf-α by macrophages is necessary for functional spinal cord regeneration in zebrafish

Spinal cord injury leads to a massive response of innate immune cells (microglia, macrophages, neutrophils) both, in non-regenerating mammals and in successfully regenerating zebrafish, but the role of these immune cells in functional spinal cord regeneration in zebrafish has not been addressed. Here we show that inhibiting inflammation reduces and promoting it accelerates axonal regeneration in larval zebrafish. Mutant analyses show that peripheral macrophages, but not neutrophils or microglia, are necessary and sufficient for full regeneration. Macrophage-less irf8 mutants show prolonged inflammation with elevated levels of Il-1{beta} and Tnf-. Decreasing Il-1{beta} levels or number of Il-1{beta}+ neutrophils rescues functional regeneration in irf8 mutants. However, during early regeneration, interference with Il-1{beta} function impairs regeneration in irf8 and wildtype animals. Inhibiting Tnf- does not rescue axonal growth in irf8 mutants, but impairs it in wildtype animals, indicating a pro-regenerative role of Tnf-. Hence, inflammation is tightly and dynamically controlled by macrophages to promote functional spinal cord regeneration in zebrafish.

developmental biology↗