* joint first author # joint corresponding author

Neueste Publikationen
Mukesh Kumar, Canan Has, Khanh Lam-Kamath, Sophie Ayciriex, Deepshe Dewett, Mina Bashir, Clara Poupault, Kai Schuhmann, Henrik Thomas, Oskar Knittelfelder, Bharath Kumar Raghuraman, R Ahrends, Jens Rister#, Andrej Shevchenko#
Lipidome Unsaturation Affects the Morphology and Proteome of the Drosophila Eye.
J Proteome Res, 23(4) 1188-1199 (2024)
Open Access DOI
Organisms respond to dietary and environmental challenges by altering the molecular composition of their glycerolipids and glycerophospholipids (GPLs), which may favorably adjust the physicochemical properties of lipid membranes. However, how lipidome changes affect the membrane proteome and, eventually, the physiology of specific organs is an open question. We addressed this issue in Drosophila melanogaster, which is not able to synthesize sterols and polyunsaturated fatty acids but can acquire them from food. We developed a series of semisynthetic foods to manipulate the length and unsaturation of fatty acid moieties in GPLs and singled out proteins whose abundance is specifically affected by membrane lipid unsaturation in the Drosophila eye. Unexpectedly, we identified a group of proteins that have muscle-related functions and increased their abundances under unsaturated eye lipidome conditions. In contrast, the abundance of two stress response proteins, Turandot A and Smg5, is decreased by lipid unsaturation. Our findings could guide the genetic dissection of homeostatic mechanisms that maintain visual function when the eye is exposed to environmental and dietary challenges.

Neha Pincha Shroff✳︎, Pengfei Xu✳︎, Sangwoo Kim, Elijah R Shelton, Ben J Gross, Yucen Liu, Carlos O Gomez, Qianlin Ye, Tingsheng Yu Drennon, Jimmy K Hu, Jeremy B A Green, Otger Campàs#, Ophir D. Klein#
Proliferation-driven mechanical compression induces signalling centre formation during mammalian organ development.
Nat Cell Biol, Art. No. doi: 10.1038/s41556-024-01380-4 (2024)
Localized sources of morphogens, called signalling centres, play a fundamental role in coordinating tissue growth and cell fate specification during organogenesis. However, how these signalling centres are established in tissues during embryonic development is still unclear. Here we show that the main signalling centre orchestrating development of rodent incisors, the enamel knot (EK), is specified by a cell proliferation-driven buildup in compressive stresses (mechanical pressure) in the tissue. Direct mechanical measurements indicate that the stresses generated by cell proliferation are resisted by the surrounding tissue, creating a circular pattern of mechanical anisotropy with a region of high compressive stress at its centre that becomes the EK. Pharmacological inhibition of proliferation reduces stresses and suppresses EK formation, and application of external pressure in proliferation-inhibited conditions rescues the formation of the EK. Mechanical information is relayed intracellularly through YAP protein localization, which is cytoplasmic in the region of compressive stress that establishes the EK and nuclear in the stretched anisotropic cells that resist the pressure buildup around the EK. Together, our data identify a new role for proliferation-driven mechanical compression in the specification of a model signalling centre during mammalian organ development.

Adriano Bolondi✳︎, Benjamin K Law✳︎, Helene Kretzmer, Seher Ipek Gassaloglu, René Buschow, Christina Riemenschneider, Dian Yang, Maria Walther, Jesse V Veenvliet, Alexander Meissner#, Zachary D Smith#, Michelle M Chan#
Reconstructing axial progenitor field dynamics in mouse stem cell-derived embryoids.
Dev Cell, Art. No. doi: 10.1016/j.devcel.2024.03.024 (2024)
Open Access DOI
Embryogenesis requires substantial coordination to translate genetic programs to the collective behavior of differentiating cells, but understanding how cellular decisions control tissue morphology remains conceptually and technically challenging. Here, we combine continuous Cas9-based molecular recording with a mouse embryonic stem cell-based model of the embryonic trunk to build single-cell phylogenies that describe the behavior of transient, multipotent neuro-mesodermal progenitors (NMPs) as they commit into neural and somitic cell types. We find that NMPs show subtle transcriptional signatures related to their recent differentiation and contribute to downstream lineages through a surprisingly broad distribution of individual fate outcomes. Although decision-making can be heavily influenced by environmental cues to induce morphological phenotypes, axial progenitors intrinsically mature over developmental time to favor the neural lineage. Using these data, we present an experimental and analytical framework for exploring the non-homeostatic dynamics of transient progenitor populations as they shape complex tissues during critical developmental windows.

Oliver Kutz, Stephan Drukewitz, Alexander Krüger, Daniela Aust, Doreen William, Sandra Oster, Evelin Schröck, Gustavo Baretton, Theresa Link, Pauline Wimberger, Jan Dominik Kuhlmann
Exploring evolutionary trajectories in ovarian cancer patients by longitudinal analysis of ctDNA.
Clin Chem Lab Med, Art. No. doi: 10.1515/cclm-2023-1266 (2024)
We analysed whether temporal heterogeneity of ctDNA encodes evolutionary patterns in ovarian cancer.

Ferenc Molnár, Szabolcs Horvát, Ana R. Ribeiro Gomes, Jorge Martinez Armas, Botond Molnár, Robert F Hevner, Kenneth Knoblauch, Henry Kennedy, Zoltan Toroczkai
Predictability of cortico-cortical connections in the mammalian brain.
Network Neuroscience, 8(1) 138-157 (2024)
Open Access DOI
Despite a five order of magnitude range in size, the brains of mammals share many anatomical and functional characteristics that translate into cortical network commonalities. Here we develop a machine learning framework to quantify the degree of predictability of the weighted interareal cortical matrix. Partial network connectivity data were obtained with retrograde tract-tracing experiments generated with a consistent methodology, supplemented by projection length measurements in a nonhuman primate (macaque) and a rodent (mouse). We show that there is a significant level of predictability embedded in the interareal cortical networks of both species. At the binary level, links are predictable with an area under the ROC curve of at least 0.8 for the macaque. Weighted medium and strong links are predictable with an 85%-90% accuracy (mouse) and 70%-80% (macaque), whereas weak links are not predictable in either species. These observations reinforce earlier observations that the formation and evolution of the cortical network at the mesoscale is, to a large extent, rule based. Using the methodology presented here, we performed imputations on all area pairs, generating samples for the complete interareal network in both species. These are necessary for comparative studies of the connectome with minimal bias, both within and across species. Revealed by tract-tracing datasets, communication between the functional areas of the cortex operates via a complex, dense, and weighted network of physical connections with little apparent regularity. Although there are studies showing the existence of nonrandom topological features, their extent has not been clear. Employing a machine learning-based approach, which efficiently extracts structural models from such datasets, here we show that there is a significant amount of regularity embedded in the mammalian connectome. This regularity allows predicting interareal connections and their weights with good accuracy and can be used to infer properties of experimentally untested connections. The structural models are well learned even with small training sets, without overfitting, suggesting the existence of a low-dimensional, universal mechanism for mesoscale cortical network formation and evolution.

Otger Campàs#, Ivar Noordstra, Alpha S Yap#
Adherens junctions as molecular regulators of emergent tissue mechanics.
Nat Rev Mol Cell Biol, 25(4) 252-269 (2024)
Tissue and organ development during embryogenesis relies on the collective and coordinated action of many cells. Recent studies have revealed that tissue material properties, including transitions between fluid and solid tissue states, are controlled in space and time to shape embryonic structures and regulate cell behaviours. Although the collective cellular flows that sculpt tissues are guided by tissue-level physical changes, these ultimately emerge from cellular-level and subcellular-level molecular mechanisms. Adherens junctions are key subcellular structures, built from clusters of classical cadherin receptors. They mediate physical interactions between cells and connect biochemical signalling to the physical characteristics of cell contacts, hence playing a fundamental role in tissue morphogenesis. In this Review, we take advantage of the results of recent, quantitative measurements of tissue mechanics to relate the molecular and cellular characteristics of adherens junctions, including adhesion strength, tension and dynamics, to the emergent physical state of embryonic tissues. We focus on systems in which cell-cell interactions are the primary contributor to morphogenesis, without significant contribution from cell-matrix interactions. We suggest that emergent tissue mechanics is an important direction for future research, bridging cell biology, developmental biology and mechanobiology to provide a holistic understanding of morphogenesis in health and disease.

Bethan Clark, Aaron Hickey, Aleksandra Marconi, Bettina Fischer, Joel Elkin, Rita Mateus, M Emília Santos
Developmental plasticity and variability in the formation of egg-spots, a pigmentation ornament in the cichlid Astatotilapia calliptera.
Evol Dev, Art. No. doi: 10.1111/ede.12475 (2024)
Open Access DOI
Vertebrate pigmentation patterns are highly diverse, yet we have a limited understanding of how evolutionary changes to genetic, cellular, and developmental mechanisms generate variation. To address this, we examine the formation of a sexually-selected male ornament exhibiting inter- and intraspecific variation, the egg-spot pattern, consisting of circular yellow-orange markings on the male anal fins of haplochromine cichlid fishes. We focus on Astatotilapia calliptera, the ancestor-type species of the Malawi cichlid adaptive radiation of over 850 species. We identify a key role for iridophores in initializing egg-spot aggregations composed of iridophore-xanthophore associations. Despite adult sexual dimorphism, aggregations initially form in both males and females, with development only diverging between the sexes at later stages. Unexpectedly, we found that the timing of egg-spot initialization is plastic. The earlier individuals are socially isolated, the earlier the aggregations form, with iridophores being the cell type that responds to changes to the social environment. Furthermore, we observe apparent competitive interactions between adjacent egg-spot aggregations, which strongly suggests that egg-spot patterning results mostly from cell-autonomous cellular interactions. Together, these results demonstrate that A. calliptera egg-spot development is an exciting model for investigating pigment pattern formation at the cellular level in a system with developmental plasticity, sexual dimorphism, and intraspecific variation. As A. calliptera represents the ancestral bauplan for egg-spots, these findings provide a baseline for informed comparisons across the incredibly diverse Malawi cichlid radiation.

Paula Cubillos, Nora Ditzer, Annika Kolodziejczyk, Gustav Schwenk, Janine Hoffmann, Theresa M Schütze, Razvan Derihaci, Cahit Birdir, Johannes Em Köllner, Andreas Petzold, Mihail Sarov, Ulrich Martin, Katherine S. Long, Pauline Wimberger, Mareike Albert
The growth factor EPIREGULIN promotes basal progenitor cell proliferation in the developing neocortex.
EMBO J, Art. No. doi: 10.1038/s44318-024-00068-7 (2024)
Open Access DOI
Neocortex expansion during evolution is linked to higher numbers of neurons, which are thought to result from increased proliferative capacity and neurogenic potential of basal progenitor cells during development. Here, we show that EREG, encoding the growth factor EPIREGULIN, is expressed in the human developing neocortex and in gorilla cerebral organoids, but not in the mouse neocortex. Addition of EPIREGULIN to the mouse neocortex increases proliferation of basal progenitor cells, whereas EREG ablation in human cortical organoids reduces proliferation in the subventricular zone. Treatment of cortical organoids with EPIREGULIN promotes a further increase in proliferation of gorilla but not of human basal progenitor cells. EPIREGULIN competes with the epidermal growth factor (EGF) to promote proliferation, and inhibition of the EGF receptor abrogates the EPIREGULIN-mediated increase in basal progenitor cells. Finally, we identify putative cis-regulatory elements that may contribute to the observed inter-species differences in EREG expression. Our findings suggest that species-specific regulation of EPIREGULIN expression may contribute to the increased neocortex size of primates by providing a tunable pro-proliferative signal to basal progenitor cells in the subventricular zone.

Christine Desroches Altamirano, Moo-Koo Kang, Mareike A Jordan, Tom Borianne, Irem Dilmen, Maren Gnädig, Alexander von Appen, Alf Honigmann, Titus Franzmann, Simon Alberti
eIF4F is a thermo-sensing regulatory node in the translational heat shock response.
Mol Cell, Art. No. doi: 10.1016/j.molcel.2024.02.038 (2024)
Open Access DOI
Heat-shocked cells prioritize the translation of heat shock (HS) mRNAs, but the underlying mechanism is unclear. We report that HS in budding yeast induces the disassembly of the eIF4F complex, where eIF4G and eIF4E assemble into translationally arrested mRNA ribonucleoprotein particles (mRNPs) and HS granules (HSGs), whereas eIF4A promotes HS translation. Using in vitro reconstitution biochemistry, we show that a conformational rearrangement of the thermo-sensing eIF4A-binding domain of eIF4G dissociates eIF4A and promotes the assembly with mRNA into HS-mRNPs, which recruit additional translation factors, including Pab1p and eIF4E, to form multi-component condensates. Using extracts and cellular experiments, we demonstrate that HS-mRNPs and condensates repress the translation of associated mRNA and deplete translation factors that are required for housekeeping translation, whereas HS mRNAs can be efficiently translated by eIF4A. We conclude that the eIF4F complex is a thermo-sensing node that regulates translation during HS.

Adrian Pascal Nievergelt#, Dennis R Diener, Aliona Bogdanova, Thomas Brown, Gaia Pigino#
Protocol for precision editing of endogenous Chlamydomonas reinhardtii genes with CRISPR-Cas.
STAR Protoc, 5(1) Art. No. 102774 (2024)
Open Access DOI
CRISPR-Cas genome engineering in the unicellular green algal model Chlamydomonas reinhardtii has until recently suffered from low integration efficiencies despite traditional genetics being well established. Here, we present a protocol for efficient homology-directed knockin mutagenesis in all commonly used strains of Chlamydomonas. We describe steps for scarless integration of fusion tags and sequence modifications of almost all proteins without the need for a preceding mutant line. We further empower this genetic-editing approach by efficient crossing and highly robust screening protocols. For complete details on the use and execution of this protocol, please refer to Nievergelt et al. (2023).1.

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Silke Thüm

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