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Dive into the research topics where Ralf Schwanbeck is active.

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Featured researches published by Ralf Schwanbeck.


The Journal of Neuroscience | 2010

The Disintegrin/Metalloproteinase ADAM10 Is Essential for the Establishment of the Brain Cortex

Ellen Jorissen; Johannes Prox; Christian Bernreuther; Silvio Weber; Ralf Schwanbeck; Lutgarde Serneels; An Snellinx; Kathleen Craessaerts; Amantha Thathiah; Ina Tesseur; Udo Bartsch; Gisela Weskamp; Carl P. Blobel; Markus Glatzel; Bart De Strooper; Paul Saftig

The metalloproteinase and major amyloid precursor protein (APP) α-secretase candidate ADAM10 is responsible for the shedding of proteins important for brain development, such as cadherins, ephrins, and Notch receptors. Adam10 −/− mice die at embryonic day 9.5, due to major defects in development of somites and vasculogenesis. To investigate the function of ADAM10 in brain, we generated Adam10 conditional knock-out (cKO) mice using a Nestin-Cre promotor, limiting ADAM10 inactivation to neural progenitor cells (NPCs) and NPC-derived neurons and glial cells. The cKO mice die perinatally with a disrupted neocortex and a severely reduced ganglionic eminence, due to precocious neuronal differentiation resulting in an early depletion of progenitor cells. Premature neuronal differentiation is associated with aberrant neuronal migration and a disorganized laminar architecture in the neocortex. Neurospheres derived from Adam10 cKO mice have a disrupted sphere organization and segregated more neurons at the expense of astrocytes. We found that Notch-1 processing was affected, leading to downregulation of several Notch-regulated genes in Adam10 cKO brains, in accordance with the central role of ADAM10 in this signaling pathway and explaining the neurogenic phenotype. Finally, we found that α-secretase-mediated processing of APP was largely reduced in these neurons, demonstrating that ADAM10 represents the most important APP α-secretase in brain. Our study reveals that ADAM10 plays a central role in the developing brain by controlling mainly Notch-dependent pathways but likely also by reducing surface shedding of other neuronal membrane proteins including APP.


Development | 2011

The disintegrin/metalloproteinase Adam10 is essential for epidermal integrity and Notch-mediated signaling

Silvio Weber; Michaela T. Niessen; Johannes Prox; Renate Lüllmann-Rauch; Annika Schmitz; Ralf Schwanbeck; Carl P. Blobel; Ellen Jorissen; Bart De Strooper; Carien M. Niessen; Paul Saftig

The disintegrin and metalloproteinase Adam10 has been implicated in the regulation of key signaling pathways that determine skin morphogenesis and homeostasis. To address the in vivo relevance of Adam10 in the epidermis, we have selectively disrupted Adam10 during skin morphogenesis and in adult skin. K14-Cre driven epidermal Adam10 deletion leads to perinatal lethality, barrier impairment and absence of sebaceous glands. A reduction of spinous layers, not associated with differences in either proliferation or apoptosis, indicates that loss of Adam10 triggers a premature differentiation of spinous keratinocytes. The few surviving K14-Adam10-deleted mice and mice in which Adam10 was deleted postnatally showed loss of hair, malformed vibrissae, epidermal hyperproliferation, cyst formation, thymic atrophy and upregulation of the cytokine thymic stromal lymphopoetin (TSLP), thus indicating non cell-autonomous multi-organ disease resulting from a compromised barrier. Together, these phenotypes closely resemble skin specific Notch pathway loss-of-function phenotypes. Notch processing is indeed strongly reduced resulting in decreased levels of Notch intracellular domain fragment and functional Notch signaling. The data identify Adam10 as the major Site-2 processing enzyme for Notch in the epidermis in vivo, and thus as a central regulator of skin development and maintenance.


Mechanisms of Development | 2006

Activated Notch1 alters differentiation of embryonic stem cells into mesodermal cell lineages at multiple stages of development.

Timm Schroeder; Franziska Meier-Stiegen; Ralf Schwanbeck; Hanna M. Eilken; Satomi Nishikawa; Robert Häsler; Stefan Schreiber; Georg W. Bornkamm; Shin-Ichi Nishikawa; Ursula Just

Signals of Notch transmembrane receptors function to regulate a wide variety of developmental cell fates. Here we investigate the role of Notch signaling in the development of mesodermal cell types by expressing a tamoxifen-inducible, activated form of Notch1 in embryonic stem cells (ESC). For differentiation of ESC into first mesodermal progenitor cells and then endothelial, mural, cardiac muscle and hematopoietic cells, the OP9 stroma co-culture system was used. Timed activation of Notch signaling by the addition of tamoxifen at various stages during differentiation of ESC into mesodermal cell lineages results in profound alterations in the generation of all of these cells. Differentiation of ESC into Flk1(+) mesodermal cells is inhibited by activated Notch. When Notch signaling is activated in mesodermal cells, generation of cardiac muscle, endothelial and hematopoietic cells is inhibited, favoring the generation of mural cells. Activation of Notch signaling in hematopoietic cells reduces colony formation and maintenance of hematopoiesis. These data suggest that Notch signaling plays a regulatory role in mesodermal development, cardiomyogenesis, the balanced generation of endothelial versus mural cells of blood vessels and hematopoietic development.


European Journal of Cell Biology | 2011

The Notch signaling pathway: molecular basis of cell context dependency.

Ralf Schwanbeck; Simone Martini; Kristina Bernoth; Ursula Just

Notch receptor signaling controls cell-fate specification, self-renewal, differentiation, proliferation and apoptosis throughout development and regeneration in all animal species studied to date. Its dysfunction causes several developmental defects and diseases in the adult. A key feature of Notch signaling is its remarkable cell-context dependency. In this review, we summarize the influences of the cellular context that regulate Notch activity and propose a model how the interplay between the cell-intrinsically established chromatin state and the cell-extrinsic signals that modify chromatin may select for Notch target accessibility and activation in different cellular contexts.


PLOS ONE | 2010

Activated Notch1 Target Genes during Embryonic Cell Differentiation Depend on the Cellular Context and Include Lineage Determinants and Inhibitors

Franziska Meier-Stiegen; Ralf Schwanbeck; Kristina Bernoth; Simone Martini; Thomas Hieronymus; David J. Ruau; Martin Zenke; Ursula Just

Background Notch receptor signaling controls developmental cell fates in a cell-context dependent manner. Although Notch signaling directly regulates transcription via the RBP-J/CSL DNA binding protein, little is known about the target genes that are directly activated by Notch in the respective tissues. Methodology/Principal Findings To analyze how Notch signaling mediates its context dependent function(s), we utilized a Tamoxifen-inducible system to activate Notch1 in murine embryonic stem cells at different stages of mesodermal differentiation and performed global transcriptional analyses. We find that the majority of genes regulated by Notch1 are unique for the cell type and vary widely dependent on other signals. We further show that Notch1 signaling regulates expression of genes playing key roles in cell differentiation, cell cycle control and apoptosis in a context dependent manner. In addition to the known Notch1 targets of the Hes and Hey families of transcriptional repressors, Notch1 activates the expression of regulatory transcription factors such as Sox9, Pax6, Runx1, Myf5 and Id proteins that are critically involved in lineage decisions in the absence of protein synthesis. Conclusion/Significance We suggest that Notch signaling determines lineage decisions and expansion of stem cells by directly activating both key lineage specific transcription factors and their repressors (Id and Hes/Hey proteins) and propose a model by which Notch signaling regulates cell fate commitment and self renewal in dependence of the intrinsic and extrinsic cellular context.


Cellular and Molecular Life Sciences | 2012

Tetraspanin15 regulates cellular trafficking and activity of the ectodomain sheddase ADAM10

Johannes Prox; Michael Willenbrock; Silvio Weber; Tobias Lehmann; Dirk Schmidt-Arras; Ralf Schwanbeck; Paul Saftig; Michael Schwake

A disintegrin and metalloproteinase10 (ADAM10) has been implicated as a major sheddase responsible for the ectodomain shedding of a number of important surface molecules including the amyloid precursor protein and cadherins. Despite a well-documented role of ADAM10 in health and disease, little is known about the regulation of this protease. To address this issue we conducted a split-ubiquitin yeast two-hybrid screen to identify membrane proteins that interact with ADAM10. The yeast experiments and co-immunoprecipitation studies in mammalian cell lines revealed tetraspanin15 (TSPAN15) to specifically associate with ADAM10. Overexpression of TSPAN15 or RNAi-mediated knockdown of TSPAN15 led to significant changes in the maturation process and surface expression of ADAM10. Expression of an endoplasmic reticulum (ER) retention mutant of TSPAN15 demonstrated an interaction with ADAM10 already in the ER. Pulse-chase experiments confirmed that TSPAN15 accelerates the ER-exit of the ADAM10–TSPAN15 complex and stabilizes the active form of ADAM10 at the cell surface. Importantly, TSPAN15 also showed the ability to mediate the regulation of ADAM10 protease activity exemplified by an increased shedding of N-cadherin and the amyloid precursor protein. In conclusion, our data show that TSPAN15 is a central modulator of ADAM10-mediated ectodomain shedding. Therapeutic manipulation of its expression levels may be an additional approach to specifically regulate the activity of the amyloid precursor protein alpha-secretase ADAM10.


Stem Cells | 2013

A Critical Role for Sox9 in Notch‐Induced Astrogliogenesis and Stem Cell Maintenance

Simone Martini; Kristina Bernoth; Heather Main; Germán C. Ortega; Urban Lendahl; Ursula Just; Ralf Schwanbeck

Notch signaling is a key regulator of cell‐fate decisions and is essential for proper neuroectodermal development. There, it favors the formation of ectoderm, promotes maintenance of neural stem cells, inhibits differentiation into neurons, and commits neural progenitors to a glial fate. In this report, we explore downstream effects of Notch important for astroglial differentiation. Transient activation of Notch1 during early stages of neuroectodermal differentiation of embryonic stem cells resulted in an increase of neural stem cells, a reduction in neurons, an induction of astroglial cell differentiation, and an induction of neural crest (NC) development. Transient or continuous activation of Notch1 during neuroectodermal differentiation led to upregulation of Sox9 expression. Knockdown of the Notch1‐induced Sox9 expression reversed Notch1‐induced astroglial cell differentiation, increase in neural stem cells, and the decrease in neurons, whereas the Notch1 effects on NC development were hardly affected by knockdown of Sox9 expression. These findings reveal a critical role for Notch‐mediated upregulation of Sox9 in a select set of neural lineage determination steps controlled by Notch. STEM CELLS 2013;31:741–751


Journal of Cellular Physiology | 2015

The role of epigenetic mechanisms in Notch signaling during development.

Ralf Schwanbeck

The Notch pathway is a highly conserved cell–cell communication pathway in metazoan involved in numerous processes during embryogenesis, development, and adult organisms. Ligand‐receptor interaction of Notch components on adjacent cells facilitates controlled sequential proteolytic cleavage resulting in the nuclear translocation of the intracellular domain of Notch (NICD). There it binds to the Notch effector protein RBP‐J, displaces a corepressor complex and enables the induction of target genes by recruitment of coactivators in a cell‐context dependent manner. Both, the gene‐specific repression and the context dependent activation require an intense communication with the underlying chromatin of the regulatory regions. Since the epigenetic landscape determines the function of the genome, processes like cell fate decision, differentiation, and self‐renewal depend on chromatin structure and its remodeling during development. In this review, structural features enabling the Notch pathway to read these epigenetic marks by proteins interacting with RBP‐J/Notch will be discussed. Furthermore, mechanisms of the Notch pathway to write and erase chromatin marks like histone acetylation and methylation are depicted as well as ATP‐dependent chromatin remodeling during the activation of target genes. An additional fine‐tuning of transcriptional regulation upon Notch activation seems to be controlled by the commitment of miRNAs. Since cells within an organism have to react to environmental changes, and developmental and differentiation cues in a proper manner, different signaling pathways have to crosstalk to each other. The chromatin status may represent one major platform to integrate these different pathways including the canonical Notch signaling. J. Cell. Physiol. 230: 969–981, 2015.


Cells Tissues Organs | 2008

Notch Signaling in Embryonic and Adult Myelopoiesis

Ralf Schwanbeck; Timm Schroeder; Konstanze Henning; Hella Kohlhof; Nikolaus Rieber; Maria-Luise Erfurth; Ursula Just

Notch signaling is a highly conserved mechanism of intercellular communication that controls the developmental fate in all animal species studied to date. Specific transmembrane ligands activate Notch receptors on neighboring cells, thereby inducing proteolytic cleavage and nuclear translocation of the Notch intracellular domain (NotchIC). NotchIC associates with the transcriptional repressor RBP-J (recombination recognition sequence binding protein at the Jĸ site), also known as CSL [CBF1/Su(H)/Lag-1], and converts it to an activator. In conjunction with chromatin remodeling enzymes, components of the transcriptional machinery and the activity of other cofactors, NotchIC induces transcription of downstream target genes, including genes of the Hes (hairy and enhancer of split) and Hey (also called Hes-related repressor Herp, Hesr, Hrt, CHF, gridlock) family. Recent evidence has shown that the Notch pathway is involved in multiple aspects of hematopoietic development. In this review, we summarize the current knowledge of the components and mechanisms of the Notch signaling pathway and discuss the role of Notch in embryonic and adult myelopoiesis. Finally, we will focus on mediators of Notch signaling in the hematopoietic system. We propose that besides suppression of differentiation mediated by the Hes/Hey family, Notch/ RBP-J signaling mediates lineage decisions by direct activation of transcription factors such as PU.1, that are critically involved in directing cells along certain cell lineages, and further influences maturation by activation of functional genes, for example β-globin.


Journal of Biological Chemistry | 2014

The Amino Acid Exchange R28E in Ciliary Neurotrophic Factor (CNTF) Abrogates Interleukin-6 Receptor-dependent but Retains CNTF Receptor-dependent Signaling via Glycoprotein 130 (gp130)/Leukemia Inhibitory Factor Receptor (LIFR)

Eva-Maria Wagener; Matthias Aurich; Samadhi Aparicio-Siegmund; Doreen M. Floss; Christoph Garbers; Kati Breusing; Björn Rabe; Ralf Schwanbeck; Joachim Grötzinger; Stefan Rose-John; Jürgen Scheller

Background: CNTF signaling is mediated by CNTFR or IL-6R in complex with gp130 and LIFR. Results: The CNTFR variant CV-1 is CNTFR-selective. Conclusion: The single amino acid exchange R28E within CNTF abrogated IL-6R binding. Significance: CV-1 allows discrimination between CNTFR- and IL-6R-mediated effects in vivo. Ciliary neurotrophic factor (CNTF) is a neurotrophic factor with therapeutic potential for neurodegenerative diseases. Moreover, therapeutic application of CNTF reduced body weight in mice and humans. CNTF binds to high or low affinity receptor complexes consisting of CNTFR·gp130·LIFR or IL-6R·gp130·LIFR, respectively. Clinical studies of the CNTF derivative Axokine revealed intolerance at higher concentrations, which may rely on the low-affinity binding of CNTF to the IL-6R. Here, we aimed to generate a CNTFR-selective CNTF variant (CV). CV-1 contained the single amino acid exchange R28E. Arg28 is in close proximity to the CNTFR binding site. Using molecular modeling, we hypothesized that Arg28 might contribute to IL-6R/CNTFR plasticity of CNTF. CV-2 to CV-5 were generated by transferring parts of the CNTFR-binding site from cardiotrophin-like cytokine to CNTF. Cardiotrophin-like cytokine selectively signals via the CNTFR·gp130·LIFR complex, albeit with a much lower affinity compared with CNTF. As shown by immunoprecipitation, all CNTF variants retained the ability to bind to CNTFR. CV-1, CV-2, and CV-5, however, lost the ability to bind to IL-6R. Although all variants induced cytokine-dependent cellular proliferation and STAT3 phosphorylation via CNTFR·gp130·LIFR, only CV-3 induced STAT3 phosphorylation via IL-6R·gp130·LIFR. Quantification of CNTF-dependent proliferation of CNTFR·gp130·LIFR expressing cells indicated that only CV-1 was as biologically active as CNTF. Thus, the CNTFR-selective CV-1 will allow discriminating between CNTFR- and IL-6R-mediated effects in vivo.

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Thomas Valerius

University of Erlangen-Nuremberg

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