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Publications in Molecular Biology by NOMIS researchers

Atlas of amnion development during the first trimester of human pregnancy

NOMIS Researcher(s)

Published in

July 14, 2025

The amnion is a critical extra-embryonic structure that supports foetal development, yet its ontogeny remains poorly defined. Here, using single-cell transcriptomics, we identified major cell types and subtypes in the human amnion across the first trimester of pregnancy, broadly categorized into epithelial, mesenchymal and macrophage lineages. We uncovered epithelial–mesenchymal and epithelial–immune transitions, highlighting dynamic remodelling during early pregnancy. Our results further revealed key intercellular communication pathways, including BMP4 signalling from mesenchymal to epithelial cells and TGF-β signalling from macrophages to mesenchymal cells, suggesting coordinated interactions that drive amnion morphogenesis. In addition, integrative comparisons across humans, non-human primates and in vitro stem cell-based models reveal that stem cell-based models recapitulate various stages of amnion development, emphasizing the need for careful selection of model systems to accurately recapitulate in vivo amnion formation. Collectively, our findings provide a detailed view of amnion cellular composition and interactions, advancing our understanding of its developmental role and regenerative potential.

Research field(s)
Molecular Biology, Developmental Biology, Microbiology

DOI
10.1038/s41556-025-01696-9

Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS

NOMIS Researcher(s)

Published in

May 19, 2025

Mutations in FUS and TARDBP cause amyotrophic lateral sclerosis (ALS), but the precise mechanisms of selective motor neuron degeneration remain unresolved. To address if pathomechanisms are shared across mutations and related to either gain- or loss-of-function, we performed single-cell RNA sequencing across isogenic induced pluripotent stem cell-derived neuron types, harbouring FUS P525L, FUS R495X, TARDBP M337V mutations or FUS knockout. Transcriptional changes were far more pronounced in motor neurons than interneurons. About 20% of uniquely dysregulated motor neuron transcripts were shared across FUS mutations, half from gain-of-function. Most indicated mitochondrial impairments, with attenuated pathways shared with mutant TARDBP M337V as well as C9orf72-ALS patient motor neurons. Mitochondrial motility was impaired in ALS motor axons, even with nuclear localized FUS mutants, demonstrating shared toxic gain-of-function mechanisms across FUS- and TARDBP-ALS, uncoupled from protein mislocalization. These early mitochondrial dysfunctions unique to motor neurons may affect survival and represent therapeutic targets in ALS.

Research field(s)
Molecular Biology, Neuroscience, Biochemistry & Molecular Biology

DOI
10.1038/s41467-025-59679-1

Microtubules in Asgard archaea

NOMIS Researcher(s)

Published in

March 21, 2025
Microtubules are a hallmark of eukaryotes. Archaeal and bacterial homologs of tubulins typically form homopolymers and non-tubular superstructures. The origin of heterodimeric tubulins assembling into microtubules remains unclear.
Here, we report the discovery of microtubule-forming tubulins in Asgard archaea, the closest known relatives of eukaryotes. These Asgard tubulins (AtubA/B) are closely related to eukaryotic α/β-tubulins and the enigmatic bacterial tubulins BtubA/B. Proteomics of Candidatus Lokiarchaeum ossiferum showed that AtubA/B were highly expressed. Cryoelectron microscopy structures demonstrate that AtubA/B form eukaryote-like heterodimers, which assembled into 5-protofilament bona fide microtubules in vitro. The additional paralog AtubB2 lacks a nucleotide-binding site and competitively displaced AtubB. These AtubA/B2 heterodimers polymerized into 7-protofilament non-canonical microtubules. In a sub-population of Ca. Lokiarchaeum ossiferum cells, cryo-tomography revealed tubular structures, while expansion microscopy identified AtubA/B cytoskeletal assemblies.
Our findings suggest a pre-eukaryotic origin of microtubules and provide a framework for understanding the fundamental principles of microtubule assembly.

Partnership(s)

Research field(s)
Molecular Biology, Evolutionary Biology, Microbiology

DOI
10.1016/j.cell.2025.02.027

BMP-dependent patterning of ectoderm tissue material properties modulates lateral mesendoderm cell migration during early zebrafish gastrulation

NOMIS Researcher(s)

Published in

March 8, 2025

Cell migration is a fundamental process during embryonic development. Most studies in vivo have focused on the migration of cells using the extracellular matrix (ECM) as their substrate for migration. In contrast, much less is known about how cells migrate on other cells, as found in early embryos when the ECM has not yet formed. Here, we show that lateral mesendoderm (LME) cells in the early zebrafish gastrula use the ectoderm as their substrate for migration. We show that the lateral ectoderm is permissive for the animal-pole-directed migration of LME cells, while the ectoderm at the animal pole halts it. These differences in permissiveness depend on the lateral ectoderm being more cohesive than the animal ectoderm, a property controlled by bone morphogenetic protein (BMP) signaling within the ectoderm. Collectively, these findings identify ectoderm tissue cohesion as one critical factor in regulating LME migration during zebrafish gastrulation.

Partnership(s)
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Research field(s)
Molecular Biology, Biophysics

DOI
10.1016/j.celrep.2025.115387

Visually guided in vivo single-cell electroporation for monitoring and manipulating mammalian hippocampal neurons

NOMIS Researcher(s)

Published in

February 10, 2025

Sparse, single-cell labeling approaches enable high-resolution, high signal-to-noise recordings from subcellular compartments and intracellular organelles and allow precise manipulations of individual cells and local circuits while minimizing complex changes associated with global network manipulations. However, thus far, only a limited number of approaches have been developed to label single cells with unique combinations of genetically encoded indicators, target deep cortical structures or sustainably use the same chronic preparation for weeks. Here we developed a method to deliver plasmids selectively to single pyramidal neurons in the mouse dorsal hippocampus using two-photon visually guided in vivo single-cell electroporation to address these limitations. This method allows long-term plasmid expression in a controlled number of individual pyramidal neurons, facilitating subcellular resolution imaging, intracellular organelle tracking, monosynaptic input mapping, plasticity induction and targeted whole-cell patch-clamp recordings.

Research field(s)
Neuroscience, Molecular Biology

DOI
10.1038/s41596-024-01099-4

Persistence of spike protein at the skull-meninges-brain axis may contribute to the neurological sequelae of COVID-19

NOMIS Researcher(s)

Published in

December 11, 2024

SARS-CoV-2 infection is associated with long-lasting neurological symptoms, although the underlying mechanisms remain unclear. Using optical clearing and imaging, we observed the accumulation of SARS-CoV-2 spike protein in the skull-meninges-brain axis of human COVID-19 patients, persisting long after viral clearance. Further, biomarkers of neurodegeneration were elevated in the cerebrospinal fluid from long COVID patients, and proteomic analysis of human skull, meninges, and brain samples revealed dysregulated inflammatory pathways and neurodegeneration-associated changes. Similar distribution patterns of the spike protein were observed in SARS-CoV-2-infected mice. Injection of spike protein alone was sufficient to induce neuroinflammation, proteome changes in the skull-meninges-brain axis, anxiety-like behavior, and exacerbated outcomes in mouse models of stroke and traumatic brain injury. Vaccination reduced but did not eliminate spike protein accumulation after infection in mice. Our findings suggest persistent spike protein at the brain borders may contribute to lasting neurological sequelae of COVID-19.

Research field(s)
Molecular Biology, Virology, Immunology

DOI
10.1016/j.chom.2024.11.007

Evolution of diapause in the African turquoise killifish by remodeling the ancient gene regulatory landscape

NOMIS Researcher(s)

Published in

May 28, 2024

Suspended animation states allow organisms to survive extreme environments. The African turquoise killifish has evolved diapause as a form of suspended development to survive a complete drought. However, the mechanisms underlying the evolution of extreme survival states are unknown. To understand diapause evolution, we performed integrative multi-omics (gene expression, chromatin accessibility, and lipidomics) in the embryos of multiple killifish species. We find that diapause evolved by a recent remodeling of regulatory elements at very ancient gene duplicates (paralogs) present in all vertebrates. CRISPR-Cas9-based perturbations identify the transcription factors REST/NRSF and FOXOs as critical for the diapause gene expression program, including genes involved in lipid metabolism. Indeed, diapause shows a distinct lipid profile, with an increase in triglycerides with very-long-chain fatty acids. Our work suggests a mechanism for the evolution of complex adaptations and offers strategies to promote long-term survival by activating suspended animation programs in other species.

Research field(s)
Molecular Biology, Biochemistry & Molecular Biology, Developmental Biology, Genetics & Heredity

DOI
10.1016/j.cell.2024.04.048

Solutes unmask differences in clustering versus phase separation of FET proteins

NOMIS Researcher(s)

Published in

May 23, 2024

Phase separation and percolation contribute to phase transitions of multivalent macromolecules. Contributions of percolation are evident through the viscoelasticity of condensates and through the formation of heterogeneous distributions of nano- and mesoscale pre-percolation clusters in sub-saturated solutions. Here, we show that clusters formed in sub-saturated solutions of FET (FUS-EWSR1-TAF15) proteins are affected differently by glutamate versus chloride. These differences on the nanoscale, gleaned using a suite of methods deployed across a wide range of protein concentrations, are prevalent and can be unmasked even though the driving forces for phase separation remain unchanged in glutamate versus chloride. Strikingly, differences in anion-mediated interactions that drive clustering saturate on the micron-scale. Beyond this length scale the system separates into coexisting phases. Overall, we find that sequence-encoded interactions, mediated by solution components, make synergistic and distinct contributions to the formation of pre-percolation clusters in sub-saturated solutions, and to the driving forces for phase separation.

Research field(s)
Molecular Biology, Biological Physics, Chemistry

DOI
10.1038/s41467-024-48775-3