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Arun Pal, Dajana Grossmann, Hannes Glaß, Vitaly Zimyanin, René Günther, Marica Catinozzi, Tobias M Boeckers, Jared Sterneckert, Erik Storkebaum, Susanne Petri, Florian Wegner, Stephan W. Grill, Francisco Pan-Montojo#, Andreas Hermann#
Glycolic acid and D-lactate-putative products of DJ-1-restore neurodegeneration in FUS - and SOD1-ALS.
Life Sci Alliance, 7(8) Art. No. e202302535 (2024)
Open Access PubMed Source   

Amyotrophic lateral sclerosis (ALS) leads to death within 2-5 yr. Currently, available drugs only slightly prolong survival. We present novel insights into the pathophysiology of Superoxide Dismutase 1 (SOD1)- and in particular Fused In Sarcoma (FUS)-ALS by revealing a supposedly central role of glycolic acid (GA) and D-lactic acid (DL)-both putative products of the Parkinson's disease associated glyoxylase DJ-1. Combined, not single, treatment with GA/DL restored axonal organelle phenotypes of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was not only accompanied by restoration of mitochondrial membrane potential but even dependent on it. Despite presenting an axonal transport deficiency as well, TDP43 patient-derived MNs did not share mitochondrial depolarization and did not respond to GA/DL treatment. GA and DL also restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites, recently reported being upstream of the mitochondrial phenotypes in FUS-ALS. Whereas these data point towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different neurodegenerative diseases characterized by mitochondrial depolarization.
@article{Pal8722,
author={Arun Pal, Dajana Grossmann, Hannes Glaß, Vitaly Zimyanin, René Günther, Marica Catinozzi, Tobias M Boeckers, Jared Sterneckert, Erik Storkebaum, Susanne Petri, Florian Wegner, Stephan W. Grill, Francisco Pan-Montojo, Andreas Hermann},
title={Glycolic acid and D-lactate-putative products of DJ-1-restore neurodegeneration in FUS - and SOD1-ALS.},
journal ={Life science alliance},
volume={7},
issue ={8},
pages={null--null},
year=2024
}

Katherine Benjamin✳︎, Aneesha Bhandari✳︎, Jessica D Kepple, Rui Qi, Zhouchun Shang, Yanan Xing, Yanru An, Nannan Zhang, Yong Hou, Tanya L Crockford, Oliver McCallion, Fadi Issa, Joanna Hester, Ulrike Tillmann, Heather Harrington#, Katherine R Bull#
Multiscale topology classifies cells in subcellular spatial transcriptomics.
Nature, Art. No. doi: 10.1038/s41586-024-07563-1 (2024)
Open Access PubMed Source   

Spatial transcriptomics measures in situ gene expression at millions of locations within a tissue1, hitherto with some trade-off between transcriptome depth, spatial resolution and sample size2. Although integration of image-based segmentation has enabled impactful work in this context, it is limited by imaging quality and tissue heterogeneity. By contrast, recent array-based technologies offer the ability to measure the entire transcriptome at subcellular resolution across large samples3-6. Presently, there exist no approaches for cell type identification that directly leverage this information to annotate individual cells. Here we propose a multiscale approach to automatically classify cell types at this subcellular level, using both transcriptomic information and spatial context. We showcase this on both targeted and whole-transcriptome spatial platforms, improving cell classification and morphology for human kidney tissue and pinpointing individual sparsely distributed renal mouse immune cells without reliance on image data. By integrating these predictions into a topological pipeline based on multiparameter persistent homology7-9, we identify cell spatial relationships characteristic of a mouse model of lupus nephritis, which we validate experimentally by immunofluorescence. The proposed framework readily generalizes to new platforms, providing a comprehensive pipeline bridging different levels of biological organization from genes through to tissues.
@article{Benjamin8743,
author={Katherine Benjamin, Aneesha Bhandari, Jessica D Kepple, Rui Qi, Zhouchun Shang, Yanan Xing, Yanru An, Nannan Zhang, Yong Hou, Tanya L Crockford, Oliver McCallion, Fadi Issa, Joanna Hester, Ulrike Tillmann, Heather Harrington, Katherine R Bull},
title={Multiscale topology classifies cells in subcellular spatial transcriptomics.},
journal ={Nature},
volume={},
pages={1--1},
year=2024
}

Teije C Middelkoop#, Jonas Neipel, Caitlin E Cornell, Ronald Naumann, Lokesh G Pimpale, Frank Jülicher#, Stephan W. Grill#
A cytokinetic ring-driven cell rotation achieves Hertwig's rule in early development.
Proc Natl Acad Sci U.S.A., 121(25) Art. No. e2318838121 (2024)
Open Access PubMed Source   

Hertwig's rule states that cells divide along their longest axis, usually driven by forces acting on the mitotic spindle. Here, we show that in contrast to this rule, microtubule-based pulling forces in early Caenorhabditis elegans embryos align the spindle with the short axis of the cell. We combine theory with experiments to reveal that in order to correct this misalignment, inward forces generated by the constricting cytokinetic ring rotate the entire cell until the spindle is aligned with the cell's long axis. Experiments with slightly compressed mouse zygotes indicate that this cytokinetic ring-driven mechanism of ensuring Hertwig's rule is general for cells capable of rotating inside a confining shell, a scenario that applies to early cell divisions of many systems.
@article{Middelkoop8735,
author={Teije C Middelkoop, Jonas Neipel, Caitlin E Cornell, Ronald Naumann, Lokesh G Pimpale, Frank Jülicher, Stephan W. Grill},
title={A cytokinetic ring-driven cell rotation achieves Hertwig's rule in early development.},
journal ={Proceedings of the National Academy of Sciences of the United States of America},
volume={121},
issue ={25},
pages={null--null},
year=2024
}

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, 59(12) 1489-1505 (2024)
Open Access PubMed Source   

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.
@article{Bolondi8700,
author={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},
title={Reconstructing axial progenitor field dynamics in mouse stem cell-derived embryoids.},
journal ={Developmental cell},
volume={59},
issue ={12},
pages={1489--1505},
year=2024
}

Rasmus K Norrild, Thomas O Mason, Lars Boyens-Thiele, Soumik Ray, Joachim B Mortensen, Anatol Fritsch, Juan M Iglesias-Artola, Louise K Klausen, Emil G P Stender, Henrik Jensen, Alexander K Buell
Taylor Dispersion-Induced Phase Separation for the Efficient Characterisation of Protein Condensate Formation.
Angew Chem Int Ed Engl, 63(25) Art. No. e202404018 (2024)
Open Access PubMed Source   

Biomolecular condensates have emerged as important structures in cellular function and disease, and are thought to form through liquid-liquid phase separation (LLPS). Thorough and efficient in vitro experiments are therefore needed to elucidate the driving forces of protein LLPS and the possibility to modulate it with drugs. Here we present Taylor dispersion-induced phase separation (TDIPS), a method to robustly measure condensation phenomena using a commercially available microfluidic platform. It uses only nanoliters of sample, does not require extrinsic fluorescent labels, and is straightforward to implement. We demonstrate TDIPS by screening the phase behaviour of two proteins that form biomolecular condensates in vivo, PGL-3 and Ddx4. Uniquely accessible to this method, we find an unexpected re-entrant behaviour at very low ionic strength, where LLPS is inhibited for both proteins. TDIPS can also probe the reversibility of assemblies, which was shown for both α-synuclein and for lysozyme, relevant for health and biotechnology, respectively. Finally, we highlight how effective inhibition concentrations and partitioning of LLPS-modifying compounds can be screened highly efficiently.
@article{Norrild8729,
author={Rasmus K Norrild, Thomas O Mason, Lars Boyens-Thiele, Soumik Ray, Joachim B Mortensen, Anatol Fritsch, Juan M Iglesias-Artola, Louise K Klausen, Emil G P Stender, Henrik Jensen, Alexander K Buell},
title={Taylor Dispersion-Induced Phase Separation for the Efficient Characterisation of Protein Condensate Formation.},
journal ={Angewandte Chemie (International ed. in English)},
volume={63},
issue ={25},
pages={null--null},
year=2024
}

Zuzana Gelová✳︎, Alvaro Ingles-Prieto✳︎, Tina Bohstedt, Fabian Frommelt, Gamma Chi, Yung-Ning Chang, Julio Garcia, Gernot Wolf, Lucia Azzollini, Sara Tremolada, Andreea Scacioc, Jesper S Hansen, Iciar Serrano, Aida Droce, Jenifer Cuesta Bernal, Nicola A Burgess-Brown, Elisabeth P Carpenter, Katharina L Dürr, Peter Kristensen, Eric R Geertsma, Saša Štefanić, Lia Scarabottolo, Tabea Wiedmer, Vera Puetter, David B Sauer, Giulio Superti-Furga
Protein binder toolbox for studies of solute carrier transporters.
J Mol Biol, Art. No. doi: 10.1016/j.jmb.2024.168665 (2024)
PubMed Source   

Transporters of the solute carrier superfamily (SLCs) are responsible for the transmembrane traffic of the majority of chemical substances in cells and tissues and are therefore of fundamental biological importance. As is often the case with membrane proteins that can be heavily glycosylated, a lack of reliable high-affinity binders hinders their functional analysis. Purifying and reconstituting transmembrane proteins in their lipidic environments remains challenging and standard approaches to generate binders for multi-transmembrane proteins, such as SLCs, channels or G protein-coupled receptors (GPCRs) are lacking. While generating protein binders to 27 SLCs, we produced full length protein or cell lines as input material for binder generation by selected binder generation platforms. As a result, we obtained 525 binders for 22 SLCs. We validated the binders with a cell-based validation workflow using immunofluorescent and immunoprecipitation methods to process all obtained binders. Finally, we demonstrated the potential applications of the binders that passed our validation pipeline in structural, biochemical, and biological applications using the exemplary protein SLC12A6, an ion transporter relevant in human disease. With this work, we were able to generate easily renewable and highly specific binders against SLCs, which will greatly facilitate the study of this neglected protein family. We hope that the process will serve as blueprint for the generation of binders against the entire superfamily of SLC transporters.
@article{Gelová8737,
author={Zuzana Gelová, Alvaro Ingles-Prieto, Tina Bohstedt, Fabian Frommelt, Gamma Chi, Yung-Ning Chang, Julio Garcia, Gernot Wolf, Lucia Azzollini, Sara Tremolada, Andreea Scacioc, Jesper S Hansen, Iciar Serrano, Aida Droce, Jenifer Cuesta Bernal, Nicola A Burgess-Brown, Elisabeth P Carpenter, Katharina L Dürr, Peter Kristensen, Eric R Geertsma, Saša Štefanić, Lia Scarabottolo, Tabea Wiedmer, Vera Puetter, David B Sauer, Giulio Superti-Furga},
title={Protein binder toolbox for studies of solute carrier transporters.},
journal ={Journal of molecular biology},
volume={},
pages={null--null},
year=2024
}

Jan Gerwin✳︎, Julián Torres-Dowdall✳︎#, Thomas Brown, Axel Meyer#
Expansion and Functional Diversification of Long-Wavelength-Sensitive Opsin in Anabantoid Fishes.
J Mol Evol, Art. No. doi: 10.1007/s00239-024-10181-0 (2024)
Open Access PubMed Source   

Gene duplication is one of the most important sources of novel genotypic diversity and the subsequent evolution of phenotypic diversity. Determining the evolutionary history and functional changes of duplicated genes is crucial for a comprehensive understanding of adaptive evolution. The evolutionary history of visual opsin genes is very dynamic, with repeated duplication events followed by sub- or neofunctionalization. While duplication of the green-sensitive opsins rh2 is common in teleost fish, fewer cases of multiple duplication events of the red-sensitive opsin lws are known. In this study, we investigate the visual opsin gene repertoire of the anabantoid fishes, focusing on the five lws opsin genes found in the genus Betta. We determine the evolutionary history of the lws opsin gene by taking advantage of whole-genome sequences of nine anabantoid species, including the newly assembled genome of Betta imbellis. Our results show that at least two independent duplications of lws occurred in the Betta lineage. The analysis of amino acid sequences of the lws paralogs of Betta revealed high levels of diversification in four of the seven transmembrane regions of the lws protein. Amino acid substitutions at two key-tuning sites are predicted to lead to differentiation of absorption maxima (λmax) between the paralogs within Betta. Finally, eye transcriptomics of B. splendens at different developmental stages revealed expression shifts between paralogs for all cone opsin classes. The lws genes are expressed according to their relative position in the lws opsin cluster throughout ontogeny. We conclude that temporal collinearity of lws expression might have facilitated subfunctionalization of lws in Betta and teleost opsins in general.
@article{Gerwin8742,
author={Jan Gerwin, Julián Torres-Dowdall, Thomas Brown, Axel Meyer},
title={Expansion and Functional Diversification of Long-Wavelength-Sensitive Opsin in Anabantoid Fishes.},
journal ={Journal of molecular evolution},
volume={},
pages={1--1},
year=2024
}

Maximilian Driller, Thomas Brown, Shannon E Currie, Michael Hiller, Sylke Winkler, Martin Pippel, Christian C Voigt, Jörns Fickel, Camila J Mazzoni
A Haplotype-resolved reference genome of a long-distance migratory bat, Pipistrellus nathusii (Keyserling & Blasius, 1839).
DNA Res, Art. No. doi: 10.1093/dnares/dsae018 (2024)
Open Access PubMed Source   

We present a complete, chromosome scale reference genome for the long-distance migratory bat Pipistrellus nathusii. The genome encompasses both haplotypic sets of autosomes and separation of both sex chromosomes by utilising highly-accurate long-reads and preserving long-range phasing information through the use of 3-dimensional chromatin conformation capture sequencing (Hi-C). This genome, accompanied by a comprehensive protein-coding sequence annotation, provides a valuable genomic resource for future investigations into the genomic bases of long-distance migratory flight in bats as well as uncovering the genetic architecture, population structure and evolutionary history of Pipistrellus nathusii. The reference-quality genome presented here gives a fundamental resource to further our understanding of bat genetics and evolution, adding to the growing number of high quality genetic resources in this field. Here, we demonstrate its use in the phylogenetic reconstruction of the order Chiroptera and in particular, we present the resources to allow detailed investigations into the genetic drivers and adaptations related to long-distance migration.
@article{Driller8726,
author={Maximilian Driller, Thomas Brown, Shannon E Currie, Michael Hiller, Sylke Winkler, Martin Pippel, Christian C Voigt, Jörns Fickel, Camila J Mazzoni},
title={A Haplotype-resolved reference genome of a long-distance migratory bat, Pipistrellus nathusii (Keyserling & Blasius, 1839).},
journal ={DNA research : an international journal for rapid publication of reports on genes and genomes},
volume={},
pages={1--1},
year=2024
}

Jade Dunot✳︎, Sebastien Moreno✳︎, Carine Gandin, Paula A Pousinha, Mascia Amici, Julien Dupuis, Margarita Anisimova, Alex Winschel, Magalie Uriot, Samuel J Petshow, Maria Mensch, Ingrid Bethus, Camilla Giudici, Heike Hampel, Benedikt Wefers, Wolfgang Wurst, Ronald Naumann, Michael C Ashby, Bodo Laube, Karen Zito, Jack R Mellor, Laurent Groc, Michael Willem#, Hélène Marie#
APP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors.
Neuron, Art. No. doi: 10.1016/j.neuron.2024.05.027 (2024)
PubMed Source   

NMDA receptors (NMDARs) are ionotropic receptors crucial for brain information processing. Yet, evidence also supports an ion-flux-independent signaling mode mediating synaptic long-term depression (LTD) and spine shrinkage. Here, we identify AETA (Aη), an amyloid-β precursor protein (APP) cleavage product, as an NMDAR modulator with the unique dual regulatory capacity to impact both signaling modes. AETA inhibits ionotropic NMDAR activity by competing with the co-agonist and induces an intracellular conformational modification of GluN1 subunits. This favors non-ionotropic NMDAR signaling leading to enhanced LTD and favors spine shrinkage. Endogenously, AETA production is increased by in vivo chemogenetically induced neuronal activity. Genetic deletion of AETA production alters NMDAR transmission and prevents LTD, phenotypes rescued by acute exogenous AETA application. This genetic deletion also impairs contextual fear memory. Our findings demonstrate AETA-dependent NMDAR activation (ADNA), characterizing AETA as a unique type of endogenous NMDAR modulator that exerts bidirectional control over NMDAR signaling and associated information processing.
@article{Dunot8736,
author={Jade Dunot, Sebastien Moreno, Carine Gandin, Paula A Pousinha, Mascia Amici, Julien Dupuis, Margarita Anisimova, Alex Winschel, Magalie Uriot, Samuel J Petshow, Maria Mensch, Ingrid Bethus, Camilla Giudici, Heike Hampel, Benedikt Wefers, Wolfgang Wurst, Ronald Naumann, Michael C Ashby, Bodo Laube, Karen Zito, Jack R Mellor, Laurent Groc, Michael Willem, Hélène Marie},
title={APP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors.},
journal ={Neuron},
volume={},
pages={null--null},
year=2024
}

Rebecca A. Green✳︎#, Renat N Khaliullin✳︎, Zhiling Zhao, Stacy D Ochoa, Jeffrey M Hendel, Tiffany-Lynn Chow, HongKee Moon, Ronald J Biggs, Arshad Desai, Karen Oegema#
Automated profiling of gene function during embryonic development.
Cell, 187(12) 3141-3160 (2024)
PubMed Source   

Systematic functional profiling of the gene set that directs embryonic development is an important challenge. To tackle this challenge, we used 4D imaging of C. elegans embryogenesis to capture the effects of 500 gene knockdowns and developed an automated approach to compare developmental phenotypes. The automated approach quantifies features-including germ layer cell numbers, tissue position, and tissue shape-to generate temporal curves whose parameterization yields numerical phenotypic signatures. In conjunction with a new similarity metric that operates across phenotypic space, these signatures enabled the generation of ranked lists of genes predicted to have similar functions, accessible in the PhenoBank web portal, for ∼25% of essential development genes. The approach identified new gene and pathway relationships in cell fate specification and morphogenesis and highlighted the utilization of specialized energy generation pathways during embryogenesis. Collectively, the effort establishes the foundation for comprehensive analysis of the gene set that builds a multicellular organism.
@article{Green8723,
author={Rebecca A. Green, Renat N Khaliullin, Zhiling Zhao, Stacy D Ochoa, Jeffrey M Hendel, Tiffany-Lynn Chow, HongKee Moon, Ronald J Biggs, Arshad Desai, Karen Oegema},
title={Automated profiling of gene function during embryonic development.},
journal ={Cell},
volume={187},
issue ={12},
pages={3141--3160},
year=2024
}
✳︎ joint first authors, # joint corresponding authors
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