@article{21015, abstract = {Early embryo geometry is one of the most invariant species-specific traits, yet its role in ensuring developmental reproducibility and robustness remains underexplored. Here we show that in zebrafish, the geometry of the fertilized egg—specifically its curvature and volume—serves as a critical initial condition triggering a cascade of events that influence development. The embryo geometry guides patterned asymmetric cell divisions in the blastoderm, generating radial gradients of cell volume and nucleocytoplasmic ratio. These gradients generate mitotic phase waves, with the nucleocytoplasmic ratio determining individual cell cycle periods independently of other cells. We demonstrate that reducing cell autonomy reshapes these waves, emphasizing the instructive role of geometry-derived volume patterns in setting the intrinsic period of the cell cycle oscillator. In addition to organizing cell cycles, early embryo geometry spatially patterns zygotic genome activation at the midblastula transition, a key step in establishing embryonic autonomy. Disrupting the embryo shape alters the zygotic genome activation pattern and causes ectopic germ layer specification, underscoring the developmental significance of geometry. Together, our findings reveal a symmetry-breaking function of early embryo geometry in coordinating cell cycle and transcriptional patterning.}, author = {Mishra, Nikhil and Li, Yuting I and Hannezo, Edouard B and Heisenberg, Carl-Philipp J}, issn = {1745-2481}, journal = {Nature Physics}, pages = {139--150}, publisher = {Springer Nature}, title = {{Geometry-driven asymmetric cell divisions pattern cell cycles and zygotic genome activation in the zebrafish embryo}}, doi = {10.1038/s41567-025-03122-1}, volume = {22}, year = {2026}, } @unpublished{21291, abstract = {The complexity and specificity of movement in vertebrates is driven by a rich diversity of spinal motor and interneuron cell types. During development, eleven spinal cord progenitor domains generate an equivalent number of cardinal neuron types. How progenitor domains, individual progenitors, and post-mitotic diversity relate is still unknown. We performed high-resolution, single-progenitor cell lineage tracing in the embryonic mouse spinal cord using mosaic analysis with double markers (MADM). Our quantitative study of lineage progression revealed that spinal cord progenitors undergo highly variable numbers of proliferative, neurogenic, and gliogenic cell divisions. The nascent clonally-related neurons migrate radially over large distances, span the dorsoventral axis, and even cross the midline, demonstrating striking bilaterality. Molecular and morphometric analysis indicate high levels of progenitor multipotency, with an individual progenitor capable of producing several molecularly and morphologically distinct neuron types, as well as astrocytes. These findings redefine spinal cord development as a process in which lineage variability — rather than rigid progenitor identity — drives the generation of cellular diversity.}, author = {Gobeil, Sophie A and Da Silveira Neto, Francisco and Silvestrelli, Giulia and Smits, Matthijs Geert and Streicher, Carmen and Cheung, Giselle T and Hippenmeyer, Simon and Sweeney, Lora Beatrice Jaeger}, booktitle = {bioRxiv}, title = {{Lineage origin of spinal cord cell type diversity}}, doi = {10.64898/2026.02.12.705305}, year = {2026}, } @article{21848, abstract = {Despite the success of mRNA therapeutics, challenges remain in optimizing immune responses and minimizing side effects. Cell-specific antigen delivery may help reduce required doses and improve vaccine efficacy. In this study, we report on a targeted delivery system for mRNA to a specific subset of skin-resident antigen-presenting cells: Langerhans cells. By functionalizing lipid nanoparticles with a langerin-specific glycomimetic ligand, we achieve selective mRNA delivery to both murine and human primary Langerhans cells with minimal off-target uptake, at the same time resulting in significantly increased mRNA translation. This targeted mRNA delivery not only enhances antigen presentation and T-cell responses but also enables dose-sparing and superior antitumor immunity compared with conventional immunization in a B16-OVA tumor model. Importantly, our platform’s high compatibility with various lipid nanoparticle formulations offers a flexible and precise tool for skin-directed mRNA delivery.}, author = {Klein, Klara and Johnson, Litty and Rîca, Ramona and Sarcevic, Mirza and Carta, Gabriele and Seiser, Saskia and Elbe-Bürger, Adelheid and Langer, Freyja and Rahhal, Nowras and Rademacher, Christoph and Wawrzinek, Robert and Quattrone, Federica and Sparber, Florian}, issn = {1523-1747}, journal = {Journal of Investigative Dermatology}, publisher = {Elsevier}, title = {{Langerhans cell–targeted mRNA delivery: A strategy for dose-sparing and enhanced antitumor immunity}}, doi = {10.1016/j.jid.2026.03.026}, year = {2026}, } @unpublished{21962, abstract = {The generation of faithful cell-type diversity and correct projection neuron numbers is essential for cerebral cortex development. Corticogenesis is however susceptible to genetic interference of critical signaling pathways, including mutations in Mtor/Rptor that lead to microcephaly. How the loss of Rptor/mTORC1 function affects cortical developmental programs, at single cell level, is still unknown. Here, we utilized Mosaic Analysis with Double Markers (MADM) technology to probe Rptor gene function upon sparse single cell- or global tissue-wide ablation. We found that tissue-wide effects drive the etiology of cortical microcephaly upon loss of Rptor, rather than deficits in projection neuron genesis. Conversely, Rptor function is cell-autonomously required for postnatal projection neuron survival in a highly cell-type-specific manner. Collectively, our results suggest that the fine balance of precise cell-type-specific cell-autonomous Rptor/mTORC1 function in concert with non-cell-autonomous tissue-wide effects is essential for the development of a properly-sized cerebral cortex with accurate projection neuron diversity.}, author = {Villalba Requena, Ana and Beattie, Robert J and Pauler, Florian and Streicher, Carmen and Miranda, Osvaldo and Krausgruber, Thomas and Senekowitsch, Martin and Farlik, Matthias and Bock, Christoph and Rülicke, Thomas and Hippenmeyer, Simon}, booktitle = {bioRxiv}, title = {{Mtor/Rptor function globally prevents cortical microcephaly and cell-autonomously promotes postnatal neuron survival in cell type specific manner}}, doi = {10.64898/2026.05.01.722172}, year = {2026}, } @unpublished{21963, abstract = {The cerebral cortex consists of immense numbers of neuronal and glial cell-types derived from radial glial progenitor (RGP) cells. How RGPs generate appropriate quantities of distinct cortical cell-types to safeguard a brain of correct size, is not well understood. However, genetic aberration in human, including mutations in PTEN, lead to cortical malformation such as macrocephaly, albeit with unknown etiology. Here we utilized Mosaic Analysis with Double Markers (MADM)-based clonal analysis and single cell phenotyping to decipher the role of Pten in neurogenic and gliogenic RGP lineage progression during cortical ontogeny. While neurogenic RGP lineage progression and projection neuron production was moderately altered in the absence of Pten, cortical astrocyte production was drastically increased. Through genetic epistasis experiments we show that the loss of Pten uncouples astrocyte generation from essential growth factor signaling hubs, funneling into MAPK. Collectively, our results suggest that Pten regulates RGP lineage progression with distinct sequential functions in cortical projection neurogenesis and astrocyte production to ensure the emergence of a correctly-sized cerebral cortex.}, author = {Miranda, Osvaldo and Contreras, Ximena and Pauler, Florian and Davaatseren, Amarbayasgalan and Amberg, Nicole and Streicher, Carmen and Villalba Requena, Ana and Heger, Anna-Magdalena and Marie, Corentine and Hassan, Bassem A. and Rülicke, Thomas and Hippenmeyer, Simon}, booktitle = {bioRxiv}, title = {{Pten orchestrates neurogenic radial glia lineage progression and tunes neocortical astrocyte production}}, doi = {10.64898/2026.05.01.722191}, year = {2026}, } @article{15016, abstract = {Amphibians, by virtue of their phylogenetic position, provide invaluable insights on nervous system evolution, development, and remodeling. The genetic toolkit for amphibians, however, remains limited. Recombinant adeno-associated viral vectors (AAVs) are a powerful alternative to transgenesis for labeling and manipulating neurons. Although successful in mammals, AAVs have never been shown to transduce amphibian cells efficiently. We screened AAVs in three amphibian species—the frogs Xenopus laevis and Pelophylax bedriagae and the salamander Pleurodeles waltl—and identified at least two AAV serotypes per species that transduce neurons. In developing amphibians, AAVs labeled groups of neurons generated at the same time during development. In the mature brain, AAVrg retrogradely traced long-range projections. Our study introduces AAVs as a tool for amphibian research, establishes a generalizable workflow for AAV screening in new species, and expands opportunities for cross-species comparisons of nervous system development, function, and evolution.}, author = {Jaeger, Eliza C.B. and Vijatovic, David and Deryckere, Astrid and Zorin, Nikol and Nguyen, Akemi L. and Ivanian, Georgiy and Woych, Jamie and Arnold, Rebecca C and Ortega Gurrola, Alonso and Shvartsman, Arik and Barbieri, Francesca and Toma, Florina-Alexandra and Gorbsky, Gary J. and Horb, Marko E. and Cline, Hollis T. and Shay, Timothy F. and Kelley, Darcy B. and Yamaguchi, Ayako and Shein-Idelson, Mark and Tosches, Maria Antonietta and Sweeney, Lora Beatrice Jaeger}, issn = {1878-1551}, journal = {Developmental Cell}, number = {5}, pages = {794--812.e6}, publisher = {Elsevier}, title = {{Adeno-associated viral tools to trace neural development and connectivity across amphibians}}, doi = {10.1016/j.devcel.2024.10.025}, volume = {60}, year = {2025}, } @misc{18697, abstract = {The information-processing capability of the brain’s cellular network depends on the physical wiring pattern between neurons and their molecular and functional characteristics. Mapping neurons and resolving their individual synaptic connections can be achieved by volumetric imaging at nanoscale resolution with dense cellular labelling. Light microscopy is uniquely positioned to visualize specific molecules but dense, synapse-level circuit reconstruction by light microscopy has been out of reach due to limitations in resolution, contrast, and volumetric imaging capability. Here we developed light-microscopy based connectomics (LICONN). We integrated specifically engineered hydrogel embedding and expansion with comprehensive deep-learning based segmentation and analysis of connectivity, thus directly incorporating molecular information in synapse-level brain tissue reconstructions. LICONN will allow synapse-level brain tissue phenotyping in biological experiments in a readily adoptable manner.}, author = {Danzl, Johann G and Lyudchik, Julia and Kreuzinger, Caroline}, publisher = {Institute of Science and Technology Austria}, title = {{Light-microscopy based connectomic reconstruction of mammalian brain tissue}}, doi = {10.15479/AT:ISTA:18697}, year = {2025}, } @article{18778, abstract = {Transcription by RNA polymerase II (Pol II) can be repressed by noncoding RNA, including the human RNA Alu. However, the mechanism by which endogenous RNAs repress transcription remains unclear. Here we present cryogenic-electron microscopy structures of Pol II bound to Alu RNA, which reveal that Alu RNA mimics how DNA and RNA bind to Pol II during transcription elongation. Further, we show how distinct domains of the general transcription factor TFIIF control repressive activity. Together, we reveal how a noncoding RNA can regulate mammalian gene expression.}, author = {Tluckova, Katarina and Kaczmarek, Beata M and Testa Salmazo, Anita P and Bernecky, Carrie A}, issn = {1545-9985}, journal = {Nature Structural & Molecular Biology}, pages = {607--612}, publisher = {Springer Nature}, title = {{Mechanism of mammalian transcriptional repression by noncoding RNA}}, doi = {10.1038/s41594-024-01448-7}, volume = {32}, year = {2025}, } @article{18879, abstract = {Our brain has remarkable computational power, generating sophisticated behaviors, storing memories over an individual’s lifetime, and producing higher cognitive functions. However, little of our neuroscience knowledge covers the human brain. Is this organ truly unique, or is it a scaled version of the extensively studied rodent brain? Combining multicellular patch-clamp recording with expansion-based superresolution microscopy and full-scale modeling, we determined the cellular and microcircuit properties of the human hippocampal CA3 region, a fundamental circuit for memory storage. In contrast to neocortical networks, human hippocampal CA3 displayed sparse connectivity, providing a circuit architecture that maximizes associational power. Human synapses showed unique reliability, high precision, and long integration times, exhibiting both species- and circuit-specific properties. Together with expanded neuronal numbers, these circuit characteristics greatly enhanced the memory storage capacity of CA3. Our results reveal distinct microcircuit properties of the human hippocampus and begin to unravel the inner workings of our most complex organ. }, author = {Watson, Jake and Vargas Barroso, Victor M and Morse, Rebecca and Navas Olivé, Andrea C and Tavakoli, Mojtaba and Danzl, Johann G and Tomschik, Matthias and Rössler, Karl and Jonas, Peter M}, issn = {1097-4172}, journal = {Cell}, number = {2}, pages = {501--514.e18}, publisher = {Elsevier}, title = {{Human hippocampal CA3 uses specific functional connectivity rules for efficient associative memory}}, doi = {10.1016/j.cell.2024.11.022}, volume = {188}, year = {2025}, } @misc{18991, abstract = {Research data for the article "Learning reshapes the hippocampal representation hierarchy" from Chiossi et al. (PNAS, 2025). The data includes hippocampal CA1 unit activity and behaviour tracking of 5 Long Evans rats during the learning of an associative memory task. Detailed information can be found in the 'readme.txt' file.}, author = {Chiossi, Heloisa}, keywords = {hippocampus, electrophysiology, behavior}, publisher = {Institute of Science and Technology Austria}, title = {{Research data for the publication "Learning reshapes the hippocampal representation hierarchy"}}, doi = {10.15479/AT:ISTA:18991}, year = {2025}, } @article{19076, abstract = {For accurate perception and motor control, an animal must distinguish between sensory experiences elicited by external stimuli and those elicited by its own actions. The diversity of behaviors and their complex influences on the senses make this distinction challenging. Here, we uncover an action–cue hub that coordinates motor commands with visual processing in the brain’s first visual relay. We show that the ventral lateral geniculate nucleus (vLGN) acts as a corollary discharge center, integrating visual translational optic flow signals with motor copies from saccades, locomotion and pupil dynamics. The vLGN relays these signals to correct action-specific visual distortions and to refine perception, as shown for the superior colliculus and in a depth-estimation task. Simultaneously, brain-wide vLGN projections drive corrective actions necessary for accurate visuomotor control. Our results reveal an extended corollary discharge architecture that refines early visual transformations and coordinates actions via a distributed hub-and-spoke network to enable visual perception during action.}, author = {Vega Zuniga, Tomas A and Sumser, Anton L and Symonova, Olga and Koppensteiner, Peter and Schmidt, Florian and Jösch, Maximilian A}, issn = {1546-1726}, journal = {Nature Neuroscience}, publisher = {Springer Nature}, title = {{A thalamic hub-and-spoke network enables visual perception during action by coordinating visuomotor dynamics}}, doi = {10.1038/s41593-025-01874-w}, volume = {28}, year = {2025}, } @phdthesis{19557, author = {Schwarz, Lena A}, issn = {2663-337X}, pages = {124}, publisher = {Institute of Science and Technology Austria}, title = {{Mapping developmental dynamics of autism spectrum disorder mouse models at single-cell resolution}}, doi = {10.15479/AT-ISTA-19557}, year = {2025}, } @article{19566, abstract = {Purpose: Optic nerve crush (ONC) is a model for studying optic nerve trauma. Unilateral ONC induces massive retinal ganglion cell (RGC) degeneration in the affected eye, leading to vision loss within a month. A common assumption has been that the non-injured contralateral eye is unaffected due to the minimal retino-retinal projections of the RGCs at the chiasm. Yet, recently, microglia, the brain-resident macrophages, have shown a responsive phenotype in the contralateral eye after ONC. Whether RGC loss accompanies this phenotype is still controversial. Methods: Using the available RGCode algorithm and developing our own RGC-Quant deep-learning-based tool, we quantify RGC's total number and density across the entire retina after ONC. Results: We confirm a short-term microglia response in the contralateral eye after ONC, but this did not affect the microglia number. Furthermore, we cannot confirm the previously reported RGC loss between naïve and contralateral retinas 5 weeks after ONC induction across the commonly used Cx3cr1creERT2 and C57BL6/J mouse models. Neither sex nor the direct comparison of the RGC markers Brn3a and RBPMS, with Brn3a co-labeling, on average, 89% of the RBPMS+-cells, explained this discrepancy, suggesting that the early microglia-responsive phenotype does not have immediate consequences on the RGC number. Conclusions: Our results corroborate that unilateral optic nerve injury elicits a microglial response in the uninjured contralateral eye but without RGC loss. Therefore, the contralateral eye should be treated separately and not as an ONC control.}, author = {Schoot Uiterkamp, Florianne E and Maes, Margaret E and Alamalhoda, Mohammad and Firoozi, Arsalan and Colombo, Gloria and Siegert, Sandra}, issn = {1552-5783}, journal = {Investigative Ophthalmology & Visual Science}, number = {3}, publisher = {Association for Research in Vision and Ophthalmology}, title = {{Optic nerve crush does not induce retinal ganglion cell loss in the contralateral eye}}, doi = {10.1167/iovs.66.3.49}, volume = {66}, year = {2025}, } @article{19704, abstract = {The information-processing capability of the brain’s cellular network depends on the physical wiring pattern between neurons and their molecular and functional characteristics. Mapping neurons and resolving their individual synaptic connections can be achieved by volumetric imaging at nanoscale resolution1,2 with dense cellular labelling. Light microscopy is uniquely positioned to visualize specific molecules, but dense, synapse-level circuit reconstruction by light microscopy has been out of reach, owing to limitations in resolution, contrast and volumetric imaging capability. Here we describe light-microscopy-based connectomics (LICONN). We integrated specifically engineered hydrogel embedding and expansion with comprehensive deep-learning-based segmentation and analysis of connectivity, thereby directly incorporating molecular information into synapse-level reconstructions of brain tissue. LICONN will allow synapse-level phenotyping of brain tissue in biological experiments in a readily adoptable manner.}, author = {Tavakoli, Mojtaba and Lyudchik, Julia and Januszewski, Michał and Vistunou, Vitali and Agudelo Duenas, Nathalie and Vorlaufer, Jakob and Sommer, Christoph M and Kreuzinger, Caroline and Oliveira, Bárbara and Cenameri, Alban and Novarino, Gaia and Jain, Viren and Danzl, Johann G}, issn = {1476-4687}, journal = {Nature}, pages = {398--410}, publisher = {Springer Nature}, title = {{Light-microscopy-based connectomic reconstruction of mammalian brain tissue}}, doi = {10.1038/s41586-025-08985-1}, volume = {642}, year = {2025}, } @article{20099, abstract = {The hippocampus, critical for learning and memory, is dogmatically described as a trisynaptic circuit where dentate gyrus granule cells (GCs), CA3 pyramidal neurons (PNs), and CA1 PNs are serially connected. However, CA3 also forms an autoassociative network, and its PNs have diverse morphologies, intrinsic properties, and GC input levels. How PN subtypes compose this recurrent network is unknown. To determine the synaptic arrangement of identified CA3 PNs, we combine multicellular patch-clamp recording and post hoc morphological analysis in mouse hippocampal slices. PNs can be divided into distinct “superficial” and “deep” subclasses, the latter including previously reported “athorny” cells. Subclasses have distinct input-output transformations and asymmetric connectivity, which is more abundant from superficial to deep PNs, splitting CA3 locally into two parallel recurrent networks. Coincident spontaneous inhibition occurs frequently within but not between subclasses, implying subclass-specific inhibitory innervation. Our results suggest two separately controlled sublayers for parallel information processing in hippocampal CA3.}, author = {Watson, Jake and Vargas Barroso, Victor M and Jonas, Peter M}, issn = {2211-1247}, journal = {Cell Reports}, number = {8}, publisher = {Elsevier}, title = {{Cell-specific wiring routes information flow through hippocampal CA3}}, doi = {10.1016/j.celrep.2025.116080}, volume = {44}, year = {2025}, } @phdthesis{20117, author = {Wang, Yiqun}, issn = {2663-337X}, pages = {108}, publisher = {Institute of Science and Technology Austria}, title = {{The role of dynamin related protein 2A in cytokinin regulated plant growth and development}}, doi = {10.15479/AT-ISTA-20117}, year = {2025}, } @phdthesis{20212, author = {Miranda, Osvaldo}, isbn = {978-3-99078-063-3}, issn = {2663-337X}, keywords = {Pten, mtor, cortical development, MADM, Mapk}, pages = {119}, publisher = {Institute of Science and Technology Austria}, title = {{Unraveling the role of Pten in cortical stem cell lineage progression using MADM}}, doi = {10.15479/AT-ISTA-20212}, year = {2025}, } @article{20289, abstract = {Cell and tissue movement in development, cancer invasion, and immune response relies on chemical or mechanical guidance cues. In many systems, this behavior is locally directed by self-generated signaling gradients rather than long-range, prepatterned cues. However, how heterogeneous mixtures of cells interact nonreciprocally and navigate through self-generated gradients remains largely unexplored. Here, we introduce a theoretical framework for the self-organized chemotaxis of heterogeneous cell populations. We find that the relative chemotactic sensitivities of different cell populations control their long-time coupling and comigration dynamics, with boundary conditions such as external cell and attractant reservoirs substantially influencing the migration patterns. Our model predicts an optimal parameter regime that enables robust and colocalized migration. We test our theoretical predictions with in vitro experiments demonstrating the comigration of distinct immune cell populations, and quantitatively reproduce observed migration patterns under wild-type and perturbed conditions. Interestingly, immune cell comigration occurs close to the predicted optimal regime. Finally, we incorporate mechanical interactions into our framework, revealing a nontrivial interplay between chemotactic and mechanical nonreciprocity in driving collective migration. Together, our findings suggest that self-generated chemotaxis is a robust strategy for the navigation of mixed cell populations.}, author = {Ucar, Mehmet C and Zane, Alsberga and Alanko, Jonna H and Sixt, Michael K and Hannezo, Edouard B}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences}, number = {34}, publisher = {National Academy of Sciences}, title = {{Self-generated chemotaxis of mixed cell populations}}, doi = {10.1073/pnas.2504064122}, volume = {122}, year = {2025}, } @phdthesis{20393, author = {Kishi, Kasumi}, issn = {2663-337X}, pages = {102}, publisher = {Institute of Science and Technology Austria}, title = {{Regulation of notochord and floor plate size during mouse development}}, doi = {10.15479/AT-ISTA-20393}, year = {2025}, } @phdthesis{20467, author = {Miteva, Florianne E}, issn = {2663-337X}, pages = {99}, publisher = {Institute of Science and Technology Austria}, title = {{The role of cyclooxygenase 1 on microglial response to inflammatory stressors}}, doi = {10.15479/AT-ISTA-20467}, year = {2025}, }