Silas Boye Nissen

All Publications

• AlphaFold2 enables accurate deorphanization of ligands to single-pass receptors. Cell systems Banhos Danneskiold-Samsoe, N., Kavi, D., Jude, K. M., Nissen, S. B., Wat, L. W., Coassolo, L., Zhao, M., Santana-Oikawa, G. A., Broido, B. B., Garcia, K. C., Svensson, K. J. 2024

  Abstract

  Secreted proteins play crucial roles in paracrine and endocrine signaling; however, identifying ligand-receptor interactions remains challenging. Here, we benchmarked AlphaFold2 (AF2) as a screening approach to identify extracellular ligands to single-pass transmembrane receptors. Key to the approach is the optimization of AF2 input and output for screening ligands against receptors to predict the most probable ligand-receptor interactions. The predictions were performed on ligand-receptor pairs not used for AF2 training. We demonstrate high discriminatory power and a success rate of close to 90% for known ligand-receptor pairs and 50% for a diverse set of experimentally validated interactions. Further, we show that screen accuracy does not correlate linearly with prediction of ligand-receptor interaction. These results demonstrate a proof of concept of a rapid and accurate screening platform to predict high-confidence cell-surface receptors for a diverse set of ligands by structural binding prediction, with potentially wide applicability for the understanding of cell-cell communication.

  View details for DOI 10.1016/j.cels.2024.10.004

  View details for PubMedID 39541981

• Cluster Assembly Dynamics Drive Fidelity of Planar Cell Polarity Polarization. bioRxiv : the preprint server for biology Nissen, S. B., Weiner, A. T., Suyama, K., Bosch, P. S., Song, S., Gu, Y., Dunn, A. R., Axelrod, J. D. 2024

  Abstract

  The planar cell polarity (PCP) signaling pathway polarizes epithelial cells in the tissue plane by segregating distinct molecular subcomplexes to opposite sides of each cell, where they interact across intercellular junctions to form asymmetric clusters. The role of clustering in this process is unknown. We hypothesized that protein cluster size distributions could be used to infer the underlying molecular dynamics and function of cluster assembly and polarization. We developed a method to count the number of monomers of core PCP proteins within individual clusters in live animals, and made measurements over time and space in wild type and in strategically chosen mutants. The data demonstrate that clustering is required for polarization, and together with mathematical modeling provide evidence that cluster assembly dynamics dictate that larger clusters are more likely to be strongly asymmetric and correctly oriented. We propose that cluster assembly dynamics thereby drive fidelity of cell- and tissue-level polarization.

  View details for DOI 10.1101/2024.10.21.619498

  View details for PubMedID 39484486

• Protein phosphatase 1 regulates core PCP signaling. EMBO reports Song, S., Cho, B., Weiner, A. T., Nissen, S. B., Ojeda Naharros, I., Sanchez Bosch, P., Suyama, K., Hu, Y., He, L., Svinkina, T., Udeshi, N. D., Carr, S. A., Perrimon, N., Axelrod, J. D. 2023: e56997

  Abstract

  Planar cell polarity (PCP) signaling polarizes epithelial cells within the plane of an epithelium. Core PCP signaling components adopt asymmetric subcellular localizations within cells to both polarize and coordinate polarity between cells. Achieving subcellular asymmetry requires additional effectors, including some mediating post-translational modifications of core components. Identification of such proteins is challenging due to pleiotropy. We used mass spectrometry-based proximity labeling proteomics to identify such regulators in the Drosophila wing. We identified the catalytic subunit of protein phosphatase1, Pp1-87B, and show that it regulates core protein polarization. Pp1-87B interacts with the core protein Van Gogh and at least one serine/threonine kinase, Dco/CKIε, that is known to regulate PCP. Pp1-87B modulates Van Gogh subcellular localization and directs its dephosphorylation in vivo. PNUTS, a Pp1 regulatory subunit, also modulates PCP. While the direct substrate(s) of Pp1-87B in control of PCP is not known, our data support the model that cycling between phosphorylated and unphosphorylated forms of one or more core PCP components may regulate acquisition of asymmetry. Finally, our screen serves as a resource for identifying additional regulators of PCP signaling.

  View details for DOI 10.15252/embr.202356997

  View details for PubMedID 37975164

• Cell autonomous polarization by the planar cell polarity signaling pathway. bioRxiv : the preprint server for biology Weiner, A. T., Cho, B., Suyama, K., Axelrod, J. D. 2023

  Abstract

  Planar Cell Polarity (PCP) signaling polarizes epithelial cells in a plane orthogonal to their apical-basal axis. A core PCP signaling module both generates molecular asymmetry within cells and coordinates the direction of polarization between neighboring cells. Two subcomplexes of core proteins segregate to opposite sides of the cell, defining a polarity axis. Homodimers of the atypical cadherin Flamingo are thought to be the scaffold upon which these subcomplexes assemble and are required for intercellular polarity signaling. The central role for Flamingo homodimers in scaffolding and intercellular communication suggests that cells in which intercellular signaling via Flamingo is disabled should fail to polarize. We show that cells lacking Flamingo, or bearing a truncated Flamingo that cannot homodimerize do in fact polarize. Cell polarization requires both positive and negative feedback, and in a multicellular tissue, feedback might involve both intracellular and intercellular pathways. We identify positive and negative feedback pathways that operate cell autonomously to drive polarization.

  View details for DOI 10.1101/2023.09.26.559449

  View details for PubMedID 37808631

  View details for PubMedCentralID PMC10557733

• Protein phosphatase 1 regulates core PCP signaling. bioRxiv : the preprint server for biology Song, S., Cho, B., Weiner, A. T., Nissen, S. B., Naharros, I. O., Bosch, P. S., Suyama, K., Hu, Y., He, L., Svinkina, T., Udeshi, N. D., Carr, S. A., Perrimon, N., Axelrod, J. D. 2023

  Abstract

  PCP signaling polarizes epithelial cells within the plane of an epithelium. Core PCP signaling components adopt asymmetric subcellular localizations within cells to both polarize and coordinate polarity between cells. Achieving subcellular asymmetry requires additional effectors, including some mediating post-translational modifications of core components. Identification of such proteins is challenging due to pleiotropy. We used mass spectrometry-based proximity labeling proteomics to identify such regulators in the Drosophila wing. We identified the catalytic subunit of Protein Phosphatase1, Pp1-87B, and show that it regulates core protein polarization. Pp1-87B interacts with the core protein Van Gogh and at least one Serine/Threonine kinase, Dco/CKIε, that is known to regulate PCP. Pp1-87B modulates Van Gogh subcellular localization and directs its dephosphorylation in vivo. PNUTS, a Pp1 regulatory subunit, also modulates PCP. While the direct substrate(s) of Pp1-87B in control of PCP is not known, our data support the model that cycling between phosphorylated and unphosphorylated forms of one or more core PCP components may regulate acquisition of asymmetry. Finally, our screen serves as a resource for identifying additional regulators of PCP signaling.

  View details for DOI 10.1101/2023.09.12.556998

  View details for PubMedID 37745534

  View details for PubMedCentralID PMC10515792

• Rapid and accurate deorphanization of ligand-receptor pairs using AlphaFold. bioRxiv : the preprint server for biology Danneskiold-Samsøe, N. B., Kavi, D., Jude, K. M., Nissen, S. B., Wat, L. W., Coassolo, L., Zhao, M., Santana-Oikawa, G. A., Broido, B. B., Garcia, K. C., Svensson, K. J. 2023

  Abstract

  Secreted proteins are extracellular ligands that play key roles in paracrine and endocrine signaling, classically by binding cell surface receptors. Experimental assays to identify new extracellular ligand-receptor interactions are challenging, which has hampered the rate of novel ligand discovery. Here, using AlphaFold-multimer, we developed and applied an approach for extracellular ligand-binding prediction to a structural library of 1,108 single-pass transmembrane receptors. We demonstrate high discriminatory power and a success rate of close to 90 % for known ligand-receptor pairs where no a priori structural information is required. Importantly, the prediction was performed on de novo ligand-receptor pairs not used for AlphaFold training and validated against experimental structures. These results demonstrate proof-of-concept of a rapid and accurate computational resource to predict high-confidence cell-surface receptors for a diverse set of ligands by structural binding prediction, with potentially wide applicability for the understanding of cell-cell communication.

  View details for DOI 10.1101/2023.03.16.531341

  View details for PubMedID 36993313

  View details for PubMedCentralID PMC10055078

• Molecular mechanism of core planar cell polarity complex function elucidated with single-molecule methods Nissen, S., Weiner, A. T., Dunn, A. R., Axelrod, J. D. CELL PRESS. 2023: 59A

  View details for Web of Science ID 000989629700289

• Mapping transcriptional heterogeneity and metabolic networks in fatty livers at single-cell resolution. iScience Coassolo, L., Liu, T., Jung, Y., Taylor, N. P., Zhao, M., Charville, G. W., Nissen, S. B., Yki-Jarvinen, H., Altman, R. B., Svensson, K. J. 2023; 26 (1): 105802

  Abstract

  Non-alcoholic fatty liver disease is a heterogeneous disease with unclear underlying molecular mechanisms. Here, we perform single-cell RNA sequencing of hepatocytes and hepatic non-parenchymal cells to map the lipid signatures in mice with non-alcoholic fatty liver disease (NAFLD). We uncover previously unidentified clusters of hepatocytes characterized by either high or low srebp1 expression. Surprisingly, the canonical lipid synthesis driver Srebp1 is not predictive of hepatic lipid accumulation, suggestive of other drivers of lipid metabolism. By combining transcriptional data at single-cell resolution with computational network analyses, we find that NAFLD is associated with high constitutive androstane receptor (CAR) expression. Mechanistically, CAR interacts with four functional modules: cholesterol homeostasis, bile acid metabolism, fatty acid metabolism, and estrogen response. Nuclear expression of CAR positively correlates with steatohepatitis in human livers. These findings demonstrate significant cellular differences in lipid signatures and identify functional networks linked to hepatic steatosis in mice and humans.

  View details for DOI 10.1016/j.isci.2022.105802

  View details for PubMedID 36636354

  View details for PubMedCentralID PMC9830221

• Transcriptional heterogeneity and cell cycle regulation as central determinants of Primitive Endoderm priming ELIFE Perera, M., Nissen, S., Proks, M., Pozzi, S., Monteiro, R. S., Trusina, A., Brickman, J. M. 2022; 11

  View details for DOI 10.7554/eLife.78967

  View details for Web of Science ID 000846816900001

• Circling in on Convective Self-Aggregation JOURNAL OF GEOPHYSICAL RESEARCH-ATMOSPHERES Nissen, S., Haerter, J. O. 2021; 126 (20): e2021JD035331

  Abstract

  In radiative-convective equilibrium simulations, convective self-aggregation (CSA) is the spontaneous organization into segregated cloudy and cloud-free regions. Evidence exists for how CSA is stabilized, but how it arises favorably on large domains is not settled. Using large-eddy simulations, we link the spatial organization emerging from the interaction of cold pools (CPs) to CSA. We systematically weaken simulated rain evaporation to reduce maximal CP radii, R max , and find reducing R max causes CSA to occur earlier. We further identify a typical rain cell generation time and a minimum radius, R min , around a given rain cell, within which the formation of subsequent rain cells is suppressed. Incorporating R min and R max , we propose a toy model that captures how CSA arises earlier on large domains: when two CPs of radii r i , r j ∈ [ R min , R max ] collide, they form a new convective event. These findings imply that interactions between CPs may explain the initial stages of CSA.

  View details for DOI 10.1029/2021JD035331

  View details for Web of Science ID 000711482400005

  View details for PubMedID 35864905

  View details for PubMedCentralID PMC9285845

• Diurnal self-aggregation NPJ CLIMATE AND ATMOSPHERIC SCIENCE Haerter, J. O., Meyer, B., Nissen, S. 2020; 3 (1)

  View details for DOI 10.1038/s41612-020-00132-z

  View details for Web of Science ID 000554715600001

• Model to Link Cell Shape and Polarity with Organogenesis ISCIENCE Nielsen, B., Nissen, S., Sneppen, K., Mathiesen, J., Trusina, A. 2020; 23 (2): 100830

  Abstract

  How do flat sheets of cells form gut and neural tubes? Across systems, several mechanisms are at play: cells wedge, form actomyosin cables, or intercalate. As a result, the cell sheet bends, and the tube elongates. It is unclear to what extent each mechanism can drive tube formation on its own. To address this question, we computationally probe if one mechanism, either cell wedging or intercalation, may suffice for the entire sheet-to-tube transition. Using a physical model with epithelial cells represented by polarized point particles, we show that either cell intercalation or wedging alone can be sufficient and that each can both bend the sheet and extend the tube. When working in parallel, the two mechanisms increase the robustness of the tube formation. The successful simulations of the key features in Drosophila salivary gland budding, sea urchin gastrulation, and mammalian neurulation support the generality of our results.

  View details for DOI 10.1016/j.isci.2020.100830

  View details for Web of Science ID 000518637100036

  View details for PubMedID 31986479

  View details for PubMedCentralID PMC6994644

• Circling in on Convective Organization GEOPHYSICAL RESEARCH LETTERS Haerter, J. O., Boing, S. J., Henneberg, O., Nissen, S. 2019; 46 (12): 7024-7034

  View details for DOI 10.1029/2019GL082092

  View details for Web of Science ID 000477616300096

• Theoretical tool bridging cell polarities with development of robust morphologies ELIFE Nissen, S., Ronhild, S., Trusina, A., Sneppen, K. 2018; 7

  Abstract

  Despite continual renewal and damages, a multicellular organism is able to maintain its complex morphology. How is this stability compatible with the complexity and diversity of living forms? Looking for answers at protein level may be limiting as diverging protein sequences can result in similar morphologies. Inspired by the progressive role of apical-basal and planar cell polarity in development, we propose that stability, complexity, and diversity are emergent properties in populations of proliferating polarized cells. We support our hypothesis by a theoretical approach, developed to effectively capture both types of polar cell adhesions. When applied to specific cases of development - gastrulation and the origins of folds and tubes - our theoretical tool suggests experimentally testable predictions pointing to the strength of polar adhesion, restricted directions of cell polarities, and the rate of cell proliferation to be major determinants of morphological diversity and stability.

  View details for DOI 10.7554/eLife.38407

  View details for Web of Science ID 000452381600001

  View details for PubMedID 30477635

  View details for PubMedCentralID PMC6286147

• Silicates Eroded under Simulated Martian Conditions Effectively Kill Bacteria-A Challenge for Life on Mars FRONTIERS IN MICROBIOLOGY Bak, E. N., Larsen, M. G., Moeller, R., Nissen, S. B., Jensen, L. R., Nornberg, P., Jensen, S. J. K., Finster, K. 2017; 8: 1709

  Abstract

  The habitability of Mars is determined by the physical and chemical environment. The effect of low water availability, temperature, low atmospheric pressure and strong UV radiation has been extensively studied in relation to the survival of microorganisms. In addition to these stress factors, it was recently found that silicates exposed to simulated saltation in a Mars-like atmosphere can lead to a production of reactive oxygen species. Here, we have investigated the stress effect induced by quartz and basalt abraded in Mars-like atmospheres by examining the survivability of the three microbial model organisms Pseudomonas putida, Bacillus subtilis, and Deinococcus radiodurans upon exposure to the abraded silicates. We found that abraded basalt that had not been in contact with oxygen after abrasion killed more than 99% of the vegetative cells while endospores were largely unaffected. Exposure of the basalt samples to oxygen after abrasion led to a significant reduction in the stress effect. Abraded quartz was generally less toxic than abraded basalt. We suggest that the stress effect of abraded silicates may be caused by a production of reactive oxygen species and enhanced by transition metal ions in the basalt leading to hydroxyl radicals through Fenton-like reactions. The low survivability of the usually highly resistant D. radiodurans indicates that the effect of abraded silicates, as is ubiquitous on the Martian surface, would limit the habitability of Mars as well as the risk of forward contamination. Furthermore, the reactivity of abraded silicates could have implications for future manned missions, although the lower effect of abraded silicates exposed to oxygen suggests that the effects would be reduced in human habitats.

  View details for DOI 10.3389/fmicb.2017.01709

  View details for Web of Science ID 000410269600001

  View details for PubMedID 28955310

  View details for PubMedCentralID PMC5601068

• Four simple rules that are sufficient to generate the mammalian blastocyst PLOS BIOLOGY Nissen, S., Perera, M., Gonzalez, J., Morgani, S. M., Jensen, M. H., Sneppen, K., Brickman, J. M., Trusina, A. 2017; 15 (7): e2000737

  Abstract

  Early mammalian development is both highly regulative and self-organizing. It involves the interplay of cell position, predetermined gene regulatory networks, and environmental interactions to generate the physical arrangement of the blastocyst with precise timing. However, this process occurs in the absence of maternal information and in the presence of transcriptional stochasticity. How does the preimplantation embryo ensure robust, reproducible development in this context? It utilizes a versatile toolbox that includes complex intracellular networks coupled to cell-cell communication, segregation by differential adhesion, and apoptosis. Here, we ask whether a minimal set of developmental rules based on this toolbox is sufficient for successful blastocyst development, and to what extent these rules can explain mutant and experimental phenotypes. We implemented experimentally reported mechanisms for polarity, cell-cell signaling, adhesion, and apoptosis as a set of developmental rules in an agent-based in silico model of physically interacting cells. We find that this model quantitatively reproduces specific mutant phenotypes and provides an explanation for the emergence of heterogeneity without requiring any initial transcriptional variation. It also suggests that a fixed time point for the cells' competence of fibroblast growth factor (FGF)/extracellular signal-regulated kinase (ERK) sets an embryonic clock that enables certain scaling phenomena, a concept that we evaluate quantitatively by manipulating embryos in vitro. Based on these observations, we conclude that the minimal set of rules enables the embryo to experiment with stochastic gene expression and could provide the robustness necessary for the evolutionary diversification of the preimplantation gene regulatory network.

  View details for DOI 10.1371/journal.pbio.2000737

  View details for Web of Science ID 000406607000001

  View details for PubMedID 28700688

  View details for PubMedCentralID PMC5507476

• Publication bias and the canonization of false facts ELIFE Nissen, S., Magidson, T., Gross, K., Bergstrom, C. T. 2016; 5

  Abstract

  Science is facing a "replication crisis" in which many experimental findings cannot be replicated and are likely to be false. Does this imply that many scientific facts are false as well? To find out, we explore the process by which a claim becomes fact. We model the community's confidence in a claim as a Markov process with successive published results shifting the degree of belief. Publication bias in favor of positive findings influences the distribution of published results. We find that unless a sufficient fraction of negative results are published, false claims frequently can become canonized as fact. Data-dredging, p-hacking, and similar behaviors exacerbate the problem. Should negative results become easier to publish as a claim approaches acceptance as a fact, however, true and false claims would be more readily distinguished. To the degree that the model reflects the real world, there may be serious concerns about the validity of purported facts in some disciplines.

  View details for DOI 10.7554/eLife.21451

  View details for Web of Science ID 000391543300001

  View details for PubMedID 27995896

  View details for PubMedCentralID PMC5173326

• <i>SuperSegger</i>: robust image segmentation, analysis and lineage tracking of bacterial cells MOLECULAR MICROBIOLOGY Stylianidou, S., Brennan, C., Nissen, S. B., Kuwada, N. J., Wiggins, P. A. 2016; 102 (4): 690-700

  Abstract

  Many quantitative cell biology questions require fast yet reliable automated image segmentation to identify and link cells from frame-to-frame, and characterize the cell morphology and fluorescence. We present SuperSegger, an automated MATLAB-based image processing package well-suited to quantitative analysis of high-throughput live-cell fluorescence microscopy of bacterial cells. SuperSegger incorporates machine-learning algorithms to optimize cellular boundaries and automated error resolution to reliably link cells from frame-to-frame. Unlike existing packages, it can reliably segment microcolonies with many cells, facilitating the analysis of cell-cycle dynamics in bacteria as well as cell-contact mediated phenomena. This package has a range of built-in capabilities for characterizing bacterial cells, including the identification of cell division events, mother, daughter and neighbouring cells, and computing statistics on cellular fluorescence, the location and intensity of fluorescent foci. SuperSegger provides a variety of postprocessing data visualization tools for single cell and population level analysis, such as histograms, kymographs, frame mosaics, movies and consensus images. Finally, we demonstrate the power of the package by analyzing lag phase growth with single cell resolution.

  View details for DOI 10.1111/mmi.13486

  View details for Web of Science ID 000387757100009

  View details for PubMedID 27569113