Biology subjects

Mercker, M.

Publications and source records attributed to Mercker, M..

10 recordsLinked to original sources

bioRxiv2024

Mechanochemical Patterning Localizes the Organizer of a Luminal Epithelium

The spontaneous emergence of tissue patterns is often attributed to biochemical reaction-diffusion systems. In Hydra tissue regeneration, the formation of a Wnt signaling center serves as a well-known example of such a process. However, despite extensive research, a strictly biochemical mechanism for self-organization in Hydra remains elusive. In this study, we investigated mechanical stimuli and identified a positive feedback loop between Wnt signaling and tissue stretching. We developed a mathematical model of mechanochemical pattern formation in a closed elastic shell, representing regenerating Hydra epithelial spheroids. Our model explains how mechanical forces drive axis formation and predicts the organizers location under various perturbations, providing a more comprehensive understanding of the spatial dynamics involved. Validation by partially confining regenerating tissues showed that the organizer indeed forms in regions with the greatest stretching potential. This work highlights a novel mechanochemical mechanism for luminal epithelium patterning, suggesting that mechanical forces, in addition to biochemical signals, play a crucial role in tissue regeneration and axis specification. Our findings offer broader implications for the role of mechanical forces in tissue organization in various biological systems, opening new avenues for investigating mechanochemical feedback in development and regeneration.

developmental biology↗

bioRxiv2024

Loss or redistribution? A better way of estimating regional changes in animal distribution and numbers caused by increased human activities

O_LIA differentiated understanding of how regional human activities affect the spatial distribution and numbers of animals within specific areas of interest is of great ecological importance. Estimating these effects from empirical data is challenging however, because human activities can affect animals in qualitatively different ways and on different spatial and temporal scales. In addition, spatio-temporal animal abundance is frequently influenced by factors intrinsic and extrinsic to the area of interest, potentially confounding impact studies, e.g., based on trends. C_LIO_LIIn this study, we synergistically combined regression and mechanistic modelling to separate these different influences. We first used partial differential equations to simulate various potential animal redistribution patterns affected by regional human activities. We then selected appropriate patterns as predictors in regression-based species distribution models, together with additional anthropogenic and natural covariates. The simultaneous consideration of large-scale (number-conserving) animal reorganisation, their regional loss or gain, and the influence of additional environmental covariates eventually allowed the generation of qualitative and quantitative estimates and predictions of human-induced changes. C_LIO_LIWe exemplarily applied our approach to investigate the current and future impact of increasing offshore wind farm (OWF) implementation in the German North Sea on common murres (Uria aalge) during autumn. OWFs constructed up to 2019 reduced common murre numbers in German waters by 18.3%. If the planned OWF priority and reservation areas outlined in the German Marine Spatial Plan are implemented, the predicted loss would increase to 77.7%. Notably, these predictions did not include additional anthropogenic activities or further plans for OWF installation, which could together lead to the almost complete disappearance of common murres from the German North Sea. C_LIO_LIBy directly comparing predicted animal numbers and distributions in hypothetical scenarios with and without human pressures, the presented method allows us to measure and predict the effects of human activities on regional trends and large-scale reorganisation. This in turn helps us to quantify and predict the impact of planned human activities on wildlife, including in the context of the current rapid expansion of alternative energies. C_LI

ecology↗

bioRxiv2024

HvNotch coordinates two independent pattern forming systems during head regeneration in Hydra by supporting a lateral inhibition process restricting the tentacle system

Hydra polyps regenerate lost body parts, including the head. In addition, Hydra head tissue has organizer properties thus being able to recruit body column tissue from a host polyp to produce ectopic hydranths after transplantation. These pattern forming processes involve Notch- and Wnt/{beta}-catenin-signaling. Hydra head regeneration consists of two parts, hypostome/organizer and tentacle development. Previous work had shown that the Notch inhibitor DAPT blocks hypostome regeneration and organizer formation, but not the appearance of tentacle genes and tentacle tissue. Here we show that the {beta}-catenin inhibitor iCRT14 blocks tentacle regeneration, but not regeneration of hypostome and organizer tissue. Using RT-qPCR gene expression analyzes during head regeneration we found that DAPT inhibits HyWnt3- and HyBMP2/4 expression and expression of transcriptional repressor genes including CnGsc, Sp5 and HyHes, while increasing expression of HyBMP5/8b and the c-fos-related gene HyKayak. ICRT14 blocks expression of the tentacle specification factor HyAlx, but not expression of HyWnt3. Thus, in accordance with regeneration of two head structures we find two signaling and gene expression modules with HyWnt3 and HyBMP4 part of a hypostome/organizer module, and BMP5/8, HyAlx and {beta}-catenin part of a tentacle module. We conclude that Notch functions as an inhibitor of tentacle production to allow regeneration of hypostome/head organizer. Furthermore, with HyKayak we present a candidate target gene for HvNotch induced repressor genes. Using siRNA and the Fos/Jun-inhibitor T5224 we show that HyKayak attenuates the expression of HyWnt3. Finally, Notch signaling was not required for head regeneration of fresh water polyps of Craspedacusta. Polyps of Craspedacusta do not have tentacles and thus, after head removal only regenerate a hypostome with a crescent of nematocytes around the mouth opening. This corroborates the idea that Notch-signaling mediates between two pattern forming processes during Hydra head regeneration.

developmental biology↗

bioRxiv2024

Genetic interference with HvNotch provides new insights into the role of the Notch-signalling pathway for developmental pattern formation in Hydra

The Notch-signalling pathway plays an important role in pattern formation in Hydra. Using pharmacological Notch inhibitors (DAPT and SAHM1), it has been demonstrated that HvNotch is required for head regeneration and tentacle patterning in Hydra. HvNotch is also involved in establishing the parent-bud boundary and instructing buds to develop feet and detach from the parent. To further investigate the functions of HvNotch, we successfully constructed NICD (HvNotch intracellular domain)-overexpressing and HvNotch-knockdown transgenic Hydra strains. NICD-overexpressing transgenic Hydra showed a pronounced inhibition on the expression of predicted HvNotch-target genes, suggesting a dominant negative effect of ectopic NICD. This resulted in a "Y-shaped" phenotype, which arises from the parent-bud boundary defect seen in polyps treated with DAPT. Additionally, "multiple heads", "two-headed" and "ectopic tentacles" phenotypes were observed. The HvNotch-knockdown transgenic Hydra with reduced expression of HvNotch exhibited similar, but not identical phenotypes, with the addition of a "two feet" phenotype. Furthermore, approximately 20% of the HvNotch-knockdown polyps were unable to regenerate a new head after decapitation. We integrated these findings into a mathematical model based on long-range gradients of signalling molecules underlying sharply defined positions of HvNotch-signalling cells at the Hydra tentacle and bud boundaries.

developmental biology↗

bioRxiv2021

How Dickkopf molecules and Wnt/beta-catenin interplay to self-organise the Hydra body axis

The antagonistic interplay between canonical Wnt signalling and Dickkopf (Dkk) proteins is fundamental to tissue organisation, including stem cell differentiation and body-axis formation. Disruptions in this interaction are linked to various human diseases, yet the mechanisms enabling robust body-axis formation through {beta}-catenin/Wnt-Dkk interactions remain unclear. A key model system for Wnt-driven pattern formation is the pre-bilaterian organism Hydra, where two ancestral Dkk proteins interact with Wnt signalling to self-organise the body axis. While Hydra patterning has been extensively studied using the activator-inhibitor framework, a model integrating experimentally identified molecules has been lacking. Here, we introduce a mathematical model that incorporates both Dkks and their experimentally observed interactions with Wnt signalling. Numerical and analytical studies show that this network alone is sufficient to drive de novo body-axis formation across a broad parameter range. Our mutual inhibition model provides a biologically grounded realization of the general local-activation/long-range-inhibition (LALI) principle of de novo pattern formation, offering a mechanistic explanation for the observed Dkk and Wnt expression patterns under various conditions. Unlike previous models, it is directly grounded in experimental data, links injury response to pattern formation, and remains robust against perturbations. Author SummaryHow organisms form and regenerate complex body structures is a fundamental question in biology. In the freshwater animal Hydra, which can regenerate its entire body from a small tissue fragment, a molecular signalling system involving Wnt proteins and their inhibitors, the Dickkopf (Dkk) family, plays a central role in organising the body axis. While these molecules are known to interact, their exact roles and how they collectively shape large-scale patterns have remained unclear--especially since their activity does not fully align with established pattern formation models. In this study, we present a new mathematical model that captures the observed interactions between Wnt and two Dkk molecules in Hydra. We show that a mechanism based on mutual inhibition--rather than the traditional interplay between activator and inhibitor molecules--can explain the emergence of a stable body axis and the results of various perturbation experiments. Our work offers new insights into the design principles of biological pattern formation and emphasizes the importance of exploring alternative mechanisms beyond classical theories.

developmental biology↗

bioRxiv2021

A flexible point and variance estimator to assess bird/bat fatality from carcass searches

Estimation of bird and bat fatalities due to collision with anthropogenic structures (such as power lines or wind turbines) is an important ecological issue. However, searching for collision victims usually only detects a proportion of the true number of collided individuals. Various mortality estimators have previously been proposed to correct for this incomplete detection, based on regular carcass searches and additional field experiments. However, each estimator implies specific assumptions/restrictions, which may easily be violated in practice. In this study, we extended previous approaches and developed a versatile algorithm to compute point and variance estimates for true carcass numbers. The presented method allows for maximal flexibility in the data structure. Using simulated data, we showed that our point and variance estimators ensured unbiased estimates under various challenging data conditions. The presented method may improve the estimation of true collision numbers, as an important pre-condition for calculating collision rates and evaluating measures to reduce collision risks, and may thus provide a basis for management decisions and/or compensation actions with regard to planned or existing wind turbines and power lines.

ecology↗

bioRxiv2021

Beyond Turing: Far-from-equilibrium patterns and mechano-chemical feedback

Turing patterns are commonly understood as specific instabilities of a spatially homogeneous steady state, resulting from activator-inhibitor interaction destabilised by diffusion. We argue that this view is restrictive and its agreement with biological observations is problematic. We present two alternative to the classical Turing analysis of patterns. First, we employ the abstract framework of evolution equations to enable the study of far-from-equilibrium patterns. Second, we introduce a mechano-chemical model, with the surface on which the pattern forms being dynamic and playing an active role in the pattern formation, effectively replacing the inhibitor. We highlight the advantages of these two alternatives vis-a-vis the classical Turing analysis, and give an overview of recent results and future challenges for both approaches.

systems biology↗

bioRxiv2021

β-Catenin and canonical Wnts control two separate pattern formation systems in Hydra: Insights from mathematical modelling

The formation of body axes and apical termini is crucial for animal development. In Hydra, nuclear {beta}-catenin and Wnt3 play key roles and were previously thought to be part of a single mechanism for axis and head formation. This study challenges this view by combining mathematical modeling with experimental data. We show that {beta}-catenin and Wnt3 patterning in Hydra operate at two different scales, requiring distinct inhibitory mechanisms. {beta}-catenin, possibly interacting with other Wnts, co-ordinates axis formation, whereas Wnt3 is involved in small-scale head patterning. A double-loop reaction-diffusion model was developed, demonstrating the ability to describe patterns with divergent shapes, which single-loop models could not achieve. The previously proposed threshold mechanism for Wnt3 expression based on {beta}-catenin prepatterns could not explain the data. Our results suggest a more complex patterning mechanism in other animals, where axis and head formation may not be controlled by a single process.

developmental biology↗

bioRxiv2020

A Wnt-specific astacin proteinase controls head formation in Hydra

The Hydra head organizer acts as a signaling center that initiates and maintains the primary body axis in steady state polyps and during budding or regeneration. Wnt/beta-Catenin signaling functions as a primary cue controlling this process, but how Wnt ligand activity is locally restricted at the protein level is poorly understood. Here we report the identification of an astacin family proteinase as a Wnt processing factor. Hydra astacin-7 (HAS-7) is expressed from gland cells as an apical-distal gradient in the body column, peaking close beneath the tentacle zone. HAS-7 siRNA knockdown abrogates HyWnt3 proteolysis in the head tissue and induces a robust double axis phenotype, which is rescued by simultaneous HyWnt3 knockdown. Accordingly, double axes are also observed in conditions of increased Wnt levels as in transgenic actin::HyWnt3 and HyDkk1/2/4 siRNA treated animals. HyWnt3-induced double axes in Xenopus embryos could be rescued by co-injection of HAS-7 mRNA. Mathematical modelling combined with experimental promotor analysis indicate an indirect regulation of HAS-7 by beta-Catenin, expanding the classical Turing-type activator-inhibitor model. Our data suggest a negative regulatory function of Wnt processing astacin proteinases in the global patterning of the oral-aboral axis in Hydra.

developmental biology↗

bioRxiv2020

Computational Modelling of Cell Movements and Aggregations during Kidney Organogenesis

During early kidney organogenesis, nephron progenitor (NP) cells move from the tip to the corner region of the ureteric bud (UB) branches in order to form the pretubular aggregate, the early structure giving rise to nephron formation. Chemotaxis and cell-cell adhesion differences are believed to drive cell patterning during this critical period of organogenesis, but the spatiotemporal organization of this process is incompletely understood. We applied a Cellular Potts model to explore to how these processes contribute to directed cell movement and aggregation. Model parameters were estimated based on fitting to experimental data obtained in ex vivo kidney explant and dissociation-reaggregation organoid culture studies. Our simulations indicated that optimal enrichment and aggregation of NP cells in the UB corner niche requires chemoattractant secretion from both the UB epithelial cells and the NP cells themselves, as well as differences in cell-cell adhesion energies. Furthermore, NP cells were observed, both experimentally and by modelling, to move at higher speed in the UB corner as compared to the tip region where they originated. The existence of different cell speed domains along the UB was confirmed using self-organizing map analysis. In summary, we demonstrated the suitability of a Cellular Potts Model approach to simulate cell movement and patterning during early nephrogenesis. Further refinement of the model should allow us to recapitulate the effects of developmental changes of cell phenotypes and molecular crosstalk during organ development. Author SummaryThe emergence of tissue patterns during vertebrate development is a major interest of both experimental research and biocomputational modelling. In this study, we established a Cellular Potts Model to explore cellular processes during early kidney development. The goal was to elucidate movements and aggregations of nephron progenitor cells. These precursor cells derive from mesenchymal cells around the ureteric buds and eventually form the epithelial structure of the nephron. Moreover, we wanted to explore computationally the mechanisms how these cells segregate from metanephric mesenchyme and move towards the location where the nephron will be formed. Utilizing the Compucell3D simulation software, we developed a model which assumes that nephron progenitor movement and aggregation is governed by only two mechanisms, i.e. cell-cell adhesion differences between cell types and nephron progenitor cell chemotaxis in response to chemoattractant secretion from two sources. These sources were either the epithelial cells of a static ureteric bud and/or the nephron progenitor cells themselves. The simulations indicated faster average cell speeds near the ureteric bud corner, the target region of cell movement and aggregation, and slower speeds near the place of origin, the tip of ureteric bud. The results were validated by comparison of the model predictions with experimental data from two ex vivo embryonic kidney models and a computational optimization protocol.

systems biology↗