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Your search keyword '"Lindenhofer, Dominik"' showing total 11 results
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11 results on '"Lindenhofer, Dominik"'

2. Mislocalization of pathogenic RBM20 variants in dilated cardiomyopathy is caused by loss-of-interaction with Transportin-3

Author

Kornienko, Julia, Rodríguez-Martínez, Marta, Fenzl, Kai, Hinze, Florian, Schraivogel, Daniel, Grosch, Markus, Tunaj, Brigit, Lindenhofer, Dominik, Schraft, Laura, Kueblbeck, Moritz, Smith, Eric, Mao, Chad, Brown, Emily, Owens, Anjali, Saguner, Ardan M., Meder, Benjamin, Parikh, Victoria, Gotthardt, Michael, and Steinmetz, Lars M.

Published
2023
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3. Neutral competition explains the clonal composition of neural organoids.

Author

Pflug, Florian G., Haendeler, Simon, Esk, Christopher, Lindenhofer, Dominik, Knoblich, Jürgen A., and von Haeseler, Arndt

Subjects
PLURIPOTENT stem cells, ORGANOIDS, HUMAN stem cells, FETAL brain, NEURAL development, SURVIVAL analysis (Biometry)
Abstract

Neural organoids model the development of the human brain and are an indispensable tool for studying neurodevelopment. Whole-organoid lineage tracing has revealed the number of progenies arising from each initial stem cell to be highly diverse, with lineage sizes ranging from one to more than 20,000 cells. This high variability exceeds what can be explained by existing stochastic models of corticogenesis and indicates the existence of an additional source of stochasticity. To explain this variability, we introduce the SAN model which distinguishes Symmetrically diving, Asymmetrically dividing, and Non-proliferating cells. In the SAN model, the additional source of stochasticity is the survival time of a lineage's pool of symmetrically dividing cells. These survival times result from neutral competition within the sub-population of all symmetrically dividing cells. We demonstrate that our model explains the experimentally observed variability of lineage sizes and derive the quantitative relationship between survival time and lineage size. We also show that our model implies the existence of a regulatory mechanism which keeps the size of the symmetrically dividing cell population constant. Our results provide quantitative insight into the clonal composition of neural organoids and how it arises. This is relevant for many applications of neural organoids, and similar processes may occur in other developing tissues both in vitro and in vivo. Author summary: Organoids are tissue that is grown in vitro, but which replicates many aspects of a specific organ. Neural organoids grown from around 20,000 human pluripotent stem cells in particular replicate many aspects of the developing human brain, and have become an important tool for studying human neurodevelopment. Lineage-tracing allows the contribution of each ancestral stem cells to the organoid to be measured quantitatively. Surprisingly, these contributions vary between a single and more than 20,000 cells, which affects many applications of neural organoids. In this paper we study how these variations arise. We introduce the so-called SAN model, named after the symmetrically, asymmetrically, and non-dividing cells it distinguishes. This model explains the large variation in lineage sizes as being caused by neutral competition between symmetrically dividing cells, i.e. by random chance as cells divide and differentiate. Our model helps to understand the growth of neural organoids quantitatively, and provides way to account for the large difference in lineage sizes in applications of neural organoids. Neutral competition as the cause of large lineage size differences may also be relevant beyond neural organoids, and possibly in the development of tissue in vivo. [ABSTRACT FROM AUTHOR]

Published
2024
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4. Human blood vessel organoids as a model of diabetic vasculopathy

Author

Wimmer, Reiner A., Leopoldi, Alexandra, Aichinger, Martin, Wick, Nikolaus, Hantusch, Brigitte, Novatchkova, Maria, Taubenschmid, Jasmin, Hämmerle, Monika, Esk, Christopher, Bagley, Joshua A., Lindenhofer, Dominik, Chen, Guibin, Boehm, Manfred, Agu, Chukwuma A., Yang, Fengtang, Fu, Beiyuan, Zuber, Johannes, Knoblich, Juergen A., Kerjaschki, Dontscho, and Penninger, Josef M.

Published
2019
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5. Mislocalization of pathogenic RBM20 variants in dilated cardiomyopathy is caused by loss-of-interaction with Transportin-3

Author

Kornienko, Julia; https://orcid.org/0000-0002-7876-230X, Rodríguez-Martínez, Marta, Fenzl, Kai; https://orcid.org/0000-0001-8097-7740, Hinze, Florian, Schraivogel, Daniel, Grosch, Markus; https://orcid.org/0000-0001-9016-8920, Tunaj, Brigit, Lindenhofer, Dominik; https://orcid.org/0000-0001-8838-7163, Schraft, Laura; https://orcid.org/0009-0005-4504-8926, Kueblbeck, Moritz, Smith, Eric; https://orcid.org/0000-0002-5915-9492, Mao, Chad; https://orcid.org/0000-0002-6765-5621, Brown, Emily, Owens, Anjali, Saguner, Ardan M, Meder, Benjamin; https://orcid.org/0000-0003-0741-2633, Parikh, Victoria; https://orcid.org/0000-0002-5138-5559, Gotthardt, Michael; https://orcid.org/0000-0003-1788-3172, Steinmetz, Lars M, Kornienko, Julia; https://orcid.org/0000-0002-7876-230X, Rodríguez-Martínez, Marta, Fenzl, Kai; https://orcid.org/0000-0001-8097-7740, Hinze, Florian, Schraivogel, Daniel, Grosch, Markus; https://orcid.org/0000-0001-9016-8920, Tunaj, Brigit, Lindenhofer, Dominik; https://orcid.org/0000-0001-8838-7163, Schraft, Laura; https://orcid.org/0009-0005-4504-8926, Kueblbeck, Moritz, Smith, Eric; https://orcid.org/0000-0002-5915-9492, Mao, Chad; https://orcid.org/0000-0002-6765-5621, Brown, Emily, Owens, Anjali, Saguner, Ardan M, Meder, Benjamin; https://orcid.org/0000-0003-0741-2633, Parikh, Victoria; https://orcid.org/0000-0002-5138-5559, Gotthardt, Michael; https://orcid.org/0000-0003-1788-3172, and Steinmetz, Lars M

Abstract

Severe forms of dilated cardiomyopathy (DCM) are associated with point mutations in the alternative splicing regulator RBM20 that are frequently located in the arginine/serine-rich domain (RS-domain). Such mutations can cause defective splicing and cytoplasmic mislocalization, which leads to the formation of detrimental cytoplasmic granules. Successful development of personalized therapies requires identifying the direct mechanisms of pathogenic RBM20 variants. Here, we decipher the molecular mechanism of RBM20 mislocalization and its specific role in DCM pathogenesis. We demonstrate that mislocalized RBM20 RS-domain variants retain their splice regulatory activity, which reveals that aberrant cellular localization is the main driver of their pathological phenotype. A genome-wide CRISPR knockout screen combined with image-enabled cell sorting identified Transportin-3 (TNPO3) as the main nuclear importer of RBM20. We show that the direct RBM20-TNPO3 interaction involves the RS-domain, and is disrupted by pathogenic variants. Relocalization of pathogenic RBM20 variants to the nucleus restores alternative splicing and dissolves cytoplasmic granules in cell culture and animal models. These findings provide proof-of-principle for developing therapeutic strategies to restore RBM20's nuclear localization in RBM20-DCM patients.

Published
2023

7. Spatial organization-dependent EphA2 transcriptional responses revealed by ligand nanocalipers

Author

Verheyen, Toon, Fang, Trixy, Lindenhofer, Dominik, Wang, Yang, Akopyan, Karen, Lindqvist, Arne, Högberg, Björn, and Teixeira, Ana I

Subjects
Transcription, Genetic, AcademicSubjects/SCI00010, Cell Line, Tumor, Receptor, EphA2, Humans, DNA, RNA-Seq, Phosphorylation, Synthetic Biology and Bioengineering, Ligands, Ephrin-A5, Nanostructures
Abstract

Ligand binding induces extensive spatial reorganization and clustering of the EphA2 receptor at the cell membrane. It has previously been shown that the nanoscale spatial distribution of ligands modulates EphA2 receptor reorganization, activation and the invasive properties of cancer cells. However, intracellular signaling downstream of EphA2 receptor activation by nanoscale spatially distributed ligands has not been elucidated. Here, we used DNA origami nanostructures to control the positions of ephrin-A5 ligands at the nanoscale and investigated EphA2 activation and transcriptional responses following ligand binding. Using RNA-seq, we determined the transcriptional profiles of human glioblastoma cells treated with DNA nanocalipers presenting a single ephrin-A5 dimer or two dimers spaced 14, 40 or 100 nm apart. These cells displayed divergent transcriptional responses to the differing ephrin-A5 nano-organization. Specifically, ephrin-A5 dimers spaced 40 or 100 nm apart showed the highest levels of differential expressed genes compared to treatment with nanocalipers that do not present ephrin-A5. These findings show that the nanoscale organization of ephrin-A5 modulates transcriptional responses to EphA2 activation.

Published
2020

10. Modulation of the MAPK pathway by differential nano-spatial distribution of ephrins to Eph receptors

Author

Lindenhofer, Dominik

Abstract

Die Eph Rezeptor Familie, die größte der Rezeptor-Tyrosinkinasen, spielt eine Rolle in Zell-Zell Kommunikation und wird durch Ephrine, welche an die Zelloberfläche gebunden sind, aktiviert. Es wurde gezeigt, dass die Anordnung von Ephrin-A5 Liganden in nano-räumlicher Art und Weise die Phosphorylierung von EphA2 Rezeptoren und die invasiven Fähigkeiten von MDA-MB-231 Zellen modulieren. Wir haben die unmittelbaren Reaktionen von MDA-MB-231 Zellen auf geclusterte Ephrin-A5 Liganden im Bezug auf den HRas-Erk Signalweg untersucht. Wir haben ein System geschaffen, welches uns erlaubt die intrazellulären Effekte zu untersuchen, welche zu der unterschiedlichen invasiven Reaktion nach Stimulation mit unterschiedlich nano-räumlich variierten Ephrin-A5 Liganden führt., The Eph receptor family, the largest family of receptor tyrosine kinases, is involved in cell-cell communication and is activated by cell surface-associated ephrin ligands. Nano-spatial distribution of ephrin-A5 ligands was shown to cause differential phosphorylation of the EphA2 receptor and to regulate the invasive properties of MDA-MB-231 cells, a human breast cancer cell line. Here we investigated the initial responses of MDA-MB-231 cells upon treatment with clustered ephrin-A5 on the known target pathway HRas-Erk. We established a system that will enable us to identify the causative intracellular effects leading to this differential response of invasiveness elicited by varying nano-spatially distributed ephrin-A5 ligands.

Published
2015
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