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J.C.O'Neill*, A.C., Uzbas*, F., Antognolli*, G., Merino*, F., Draganova, K., Jäck, A., Zhang, S., Pedini, G., Schessner, J.P., Cramer, K., Schepers, A., Metzger, F., Esgleas, M., Smialowski, P., Guerrini, R., Falk, S., Feederle, R., Freytag, S., Wang, Z., Bahlo, M., Jungmann, R., Bagni, C., Borner, G.H.H., Robertson, S.P., Hauck, S.M., and Götz, M.
* equal contribution | (IMPRS-LS predocs are in bold)
Science, 2022, 376, eabf9088.
DOI: 10.1126/science.abf9088

Spatial centrosome proteome of human neural cells uncovers disease-relevant heterogeneity

The centrosome provides an intracellular anchor for the cytoskeleton, regulating cell division, cell migration, and cilia formation. We used spatial proteomics to elucidate protein interaction networks at the centrosome of human induced pluripotent stem cell-derived neural stem cells (NSCs) and neurons. Centrosome-associated proteins were largely cell type-specific, with protein hubs involved in RNA dynamics. Analysis of neurodevelopmental disease cohorts identified a significant overrepresentation of NSC centrosome proteins with variants in patients with periventricular heterotopia (PH). Expressing the PH-associated mutant pre-mRNA-processing factor 6 (PRPF6) reproduced the periventricular misplacement in the developing mouse brain, highlighting missplicing of transcripts of a microtubule-associated kinase with centrosomal location as essential for the phenotype. Collectively, cell type-specific centrosome interactomes explain how genetic variants in ubiquitous proteins may convey brain-specific phenotypes.



graduationCongratulations on your PhD!

Marius Schneider

The long non-coding RNA "upstream to Slitrk3" (RUS) affects chromatin organization by binding to Brd2 and Smarca5  

RG: Johanna Scheuermann



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Schneider, M.F., Müller, V., Müller, S.A., Lichtenthaler, S.F., Becker, P.B., and Scheuermann, J.C.
Life Sci Alliance 5.
doi: 10.26508/lsa.202201504

LncRNA RUS shapes the gene expression program towards neurogenesis

The evolution of brain complexity correlates with an increased expression of long, noncoding (lnc) RNAs in neural tissues. Although prominent examples illustrate the potential of lncRNAs to scaffold and target epigenetic regulators to chromatin loci, only few cases have been described to function during brain development. We present a first functional characterization of the lncRNA LINC01322, which we term RUS for "RNA upstream of Slitrk3." The RUS gene is well conserved in mammals by sequence and synteny next to the neurodevelopmental gene Slitrk3. RUS is exclusively expressed in neural cells and its expression increases during neuronal differentiation of mouse embryonic cortical neural stem cells. Depletion of RUS locks neuronal precursors in an intermediate state towards neuronal differentiation resulting in arrested cell cycle and increased apoptosis. RUS associates with chromatin in the vicinity of genes involved in neurogenesis, most of which change their expression upon RUS depletion. The identification of a range of epigenetic regulators as specific RUS interactors suggests that the lncRNA may mediate gene activation and repression in a highly context-dependent manner.



graduationCongratulations on your PhD!

Daan Verhagen

A novel perspective on the in vivo chromatin landscape of Saccharomyces Cerevisiae   

RG: Felix Müller-Planitz



How does cancer arise? How does cellular composition influence tumor malignancy? These questions are profound and challenging to answer, but are crucial to understand the disease and find the right cure. Now, a German-Danish team led by Professor Matthias Mann has developed a ground-breaking technology called ‘Deep Visual Proteomics’. This method provides researchers and clinicians with a protein read-out to understand cancer at single cell-type resolution. The technology was published in the journal Nature Biotechnology and demonstrates its potential in a first application to cancer cells.

Proteins are among the most important players in a variety of diseases. Aptly referred to as the 'molecular workhorses of the cell’, their proper function often determines the fitness of a cell and that of an individual by extension. Matthias Mann explains: “When something goes wrong inside our cells and we become sick, you can be sure that proteins are involved in a wide range of different ways. Because of this, mapping the protein landscape can help us determine why a tumor could develop in a particular patient, what vulnerabilities that tumor has and also what treatment strategy might prove the most beneficial.” 

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The entire genomic material of a cell must be packed into a tiny cell nucleus in such a way, that on the one hand, it can be stored in an organized manner and, on the other hand, it can be transcribed, duplicated or repaired as needed. Different proteins are responsible for space-saving packaging, which can roll up or loop the DNA. Scientists Kikuë Tachibana and Karl Duderstadt from the Max Planck Institute of Biochemistry (MPIB) in Martinsried are investigating the exact task and function of these molecular machines. They discovered that the MCM complex plays an important role in restricting DNA loop formation and thus in the three-dimensional structure of the genome and in gene regulation. The research results were published in the scientific journal Nature.

A DNA molecule is about two meters long and still has to be packed into a tiny cell nucleus. A cell nucleus is about the size of a toner particle from a printer or a fine dust particle. How does it work? How can the genetic information be stored and packaged on the one hand, but read on the other? How is it put into loops? Packaging and unpacking are also dynamic processes that must run quickly and smoothly.

Now Kikuë Tachibana, new director of the department “Totipotency” at MPIB, and her team discovered that a protein complex well known for its function in DNA replication has an unexpected role in genome folding. “During a symposium at MPIB, it emerged that my new colleague Karl Duderstadt and I shared a common interest. We decided to join forces to use complementary approaches to investigate these initial observations at a mechanistic level”. Karl Duderstadt is head of the research group "Structure and Dynamics of Molecular Machines". 

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Jocher, G., Grass, V., Tschirner, S.K., Riepler, L., Breimann, S., Kaya, T., Oelsner, M., Hamad, M.S., Hofmann, L.I., Blobel, C.P., Schmidt-Weber, C.B., Gokce, O., Jakwerth, C.A., Trimpert, J., Kimpel, J., Pichlmair, A., and Lichtenthaler, S.F.
EMBO reports, 2022, e54305.
doi: 10.15252/embr.202154305

ADAM10 and ADAM17 promote SARS-CoV-2 cell entry and spike protein-mediated lung cell fusion

The severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) is the causative agent of COVID-19, but host cell factors contributing to COVID-19 pathogenesis remain only partly understood. We identify the host metalloprotease ADAM17 as a facilitator of SARS-CoV-2 cell entry and the metalloprotease ADAM10 as a host factor required for lung cell syncytia formation, a hallmark of COVID-19 pathology. ADAM10 and ADAM17, which are broadly expressed in the human lung, cleave the SARS-CoV-2 spike protein (S) in vitro, indicating that ADAM10 and ADAM17 contribute to the priming of S, an essential step for viral entry and cell fusion. ADAM protease-targeted inhibitors severely impair lung cell infection by the SARS-CoV-2 variants of concern alpha, beta, delta, and omicron and also reduce SARS-CoV-2 infection of primary human lung cells in a TMPRSS2 protease-independent manner. Our study establishes ADAM10 and ADAM17 as host cell factors for viral entry and syncytia formation and defines both proteases as potential targets for antiviral drug development.



graduationCongratulations on your PhD!

Jakub Chrustowicz

Mechanistic studies of GID/CTLH E3 ubiquitin ligases   

RG: Brenda Schulman



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Hees, J.T., and Harbauer, A.B.
Methods Mol Biol, 2022, 2431, 225-237.
doi: 10.1007/978-1-0716-1990-2_11

Live-Cell Imaging of RNA Transport in Axons of Cultured Primary Neurons

The use of fluorescent proteins has revolutionized the study of protein localization and transport. However, the visualization of other molecules and specifically RNA during live-cell imaging remains challenging. In this chapter, we provide guidance to the available methods, their advantages and drawbacks as well as provide a detailed protocol for the detection of RNA transport using the MS2/PP7-split-Venus system for background-free RNA imaging.



"If you're going on a long journey, it's better to pack light and pack smart," says Angelika Harbauer, head of the research group Neurometabolism at the Max Planck Institute for Biological Intelligence, in foundation (i.f.). The sentence summarizes the motto by which cellular power plants known as mitochondria travel through the long extensions of nerve cells. Harbauer's research shows that, instead of a protein that is important to them, travelling mitochondria take along the blueprints needed to produce that protein. The results were published in the journal Neuron and have now been highlighted in a feature article in the journal Autophagy.

Proteins are biological machines that perform a wide variety of tasks. In one of her research projects, which started at Boston Children's Hospital in Tom Schwarz's group, Angelika Harbauer studies the production of one of these proteins in more detail. The PINK1 protein is found in mitochondria, the power plants of the cell, and ensures that defective mitochondria are sorted out and recycled. This prevents the cell from being damaged by defective mitochondria. PINK1 is needed wherever there are mitochondria. 

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