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  1. Article ; Online: The role of Xenopus developmental biology in unraveling Wnt signalling and antero-posterior axis formation.

    Niehrs, Christof

    Developmental biology

    2021  Volume 482, Page(s) 1–6

    Abstract: Wnt signalling plays an eminent role in development, stem cell growth, and tissue homeostasis. Much of what we know about Wnt signalling, we owe to research in developmental biology. Here I review some salient discoveries in the older literature, ... ...

    Abstract Wnt signalling plays an eminent role in development, stem cell growth, and tissue homeostasis. Much of what we know about Wnt signalling, we owe to research in developmental biology. Here I review some salient discoveries in the older literature, beginning with the Lithium experiments in sea urchin by Curt Herbst in the 1890ies, when unknown to him he observed the gradual effects of Wnt overactivation upon embryonic axis formation. After revisiting key discoveries into Wingless signalling in Drosophila, I examine the role that the Xenopus embryo has played as model system in this regard. Not only were components of the Wnt cascade dissected and secreted Wnt antagonists discovered in Xenopus, but it also played a key role in unveiling the evolutionary conserved role of Wnt signalling in primary body axis formation. I conclude that Xenopus developmental biology has played a major role in elucidating the mechanisms of embryonic Wnt signalling.
    MeSH term(s) Animals ; Body Patterning/physiology ; Drosophila/embryology ; Drosophila/metabolism ; Embryonic Development/physiology ; Sea Urchins/embryology ; Sea Urchins/metabolism ; Wnt Proteins/metabolism ; Wnt Signaling Pathway/physiology ; Xenopus laevis/embryology ; Xenopus laevis/metabolism
    Chemical Substances Wnt Proteins
    Language English
    Publishing date 2021-11-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1114-9
    ISSN 1095-564X ; 0012-1606
    ISSN (online) 1095-564X
    ISSN 0012-1606
    DOI 10.1016/j.ydbio.2021.11.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Lessons from the Organizer - an interview with Edward (Eddy) M. De Robertis.

    Niehrs, Christof

    The International journal of developmental biology

    2020  Volume 65, Issue 1-2-3, Page(s) 111–122

    Abstract: In this interview, we talk with developmental biologist Eddy De Robertis about his wider scientific career and the history of developmental biology in Latin America. We discuss the early days of the homeobox, the discovery of the mechanism of the Spemann- ...

    Abstract In this interview, we talk with developmental biologist Eddy De Robertis about his wider scientific career and the history of developmental biology in Latin America. We discuss the early days of the homeobox, the discovery of the mechanism of the Spemann-Mangold organizer function in
    MeSH term(s) Animals ; Genes, Homeobox ; Organizers, Embryonic ; Xenopus laevis/embryology ; Xenopus laevis/genetics
    Language English
    Publishing date 2020-08-18
    Publishing country Spain
    Document type Interview ; Research Support, Non-U.S. Gov't
    ZDB-ID 1036070-0
    ISSN 1696-3547 ; 0214-6282
    ISSN (online) 1696-3547
    ISSN 0214-6282
    DOI 10.1387/ijdb.190298cn
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  3. Article: The role of Xenopus developmental biology in unraveling Wnt signalling and antero-posterior axis formation

    Niehrs, Christof

    Developmental biology. 2022 Feb., v. 482

    2022  

    Abstract: Wnt signalling plays an eminent role in development, stem cell growth, and tissue homeostasis. Much of what we know about Wnt signalling, we owe to research in developmental biology. Here I review some salient discoveries in the older literature, ... ...

    Abstract Wnt signalling plays an eminent role in development, stem cell growth, and tissue homeostasis. Much of what we know about Wnt signalling, we owe to research in developmental biology. Here I review some salient discoveries in the older literature, beginning with the Lithium experiments in sea urchin by Curt Herbst in the 1890ies, when unknown to him he observed the gradual effects of Wnt overactivation upon embryonic axis formation. After revisiting key discoveries into Wingless signalling in Drosophila, I examine the role that the Xenopus embryo has played as model system in this regard. Not only were components of the Wnt cascade dissected and secreted Wnt antagonists discovered in Xenopus, but it also played a key role in unveiling the evolutionary conserved role of Wnt signalling in primary body axis formation. I conclude that Xenopus developmental biology has played a major role in elucidating the mechanisms of embryonic Wnt signalling.
    Keywords Drosophila ; Echinoidea ; Xenopus ; cell growth ; homeostasis ; lithium ; stem cells
    Language English
    Dates of publication 2022-02
    Size p. 1-6.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 1114-9
    ISSN 1095-564X ; 0012-1606
    ISSN (online) 1095-564X
    ISSN 0012-1606
    DOI 10.1016/j.ydbio.2021.11.006
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  4. Article ; Online: Multimodal Wnt signalling in the mouse neocortex.

    Da Silva, Fabio / Niehrs, Christof

    Cells & development

    2023  Volume 174, Page(s) 203838

    Abstract: The neocortex is the site of higher cognitive functions and its development is tightly regulated by cell signalling pathways. Wnt signalling is inexorably linked with neocortex development but its precise role remains unclear. Most studies demonstrate ... ...

    Abstract The neocortex is the site of higher cognitive functions and its development is tightly regulated by cell signalling pathways. Wnt signalling is inexorably linked with neocortex development but its precise role remains unclear. Most studies demonstrate that Wnt/β-catenin regulates neural progenitor self-renewal but others suggest it can also promote differentiation. Wnt/STOP signalling is a novel branch of the Wnt pathway that stabilizes proteins during G2/M by inhibiting glycogen synthase kinase 3 (GSK3)-mediated protein degradation. Recent data from our work in Da Silva et al. (2021) demonstrate that Wnt/STOP is involved in neocortex development where, by stabilizing the neurogenic transcription factors Sox4 and Sox11, it promotes neural progenitor differentiation. We also show that Wnt/STOP regulates asymmetric cell division and cell cycle dynamics in apical and basal progenitors, respectively. Our study reveals a division of labour in the Wnt signalling pathway by suggesting that Wnt/STOP is the primary driver of cortical neurogenesis while Wnt/β-catenin is mainly responsible for self-renewal. These results resolve a decades-old question on the role of Wnt signalling in cortical neural progenitors.
    MeSH term(s) Mice ; Animals ; Wnt Signaling Pathway ; beta Catenin/metabolism ; Wnt Proteins/metabolism ; Glycogen Synthase Kinase 3/metabolism ; Neocortex/metabolism
    Chemical Substances beta Catenin ; Wnt Proteins ; Glycogen Synthase Kinase 3 (EC 2.7.11.26)
    Language English
    Publishing date 2023-04-14
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2667-2901
    ISSN (online) 2667-2901
    DOI 10.1016/j.cdev.2023.203838
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: R-Spondin 2 governs Xenopus left-right body axis formation by establishing an FGF signaling gradient.

    Lee, Hyeyoon / Camuto, Celine Marie / Niehrs, Christof

    Nature communications

    2024  Volume 15, Issue 1, Page(s) 1003

    Abstract: Establishment of the left-right (LR, sinistral, dextral) body axis in many vertebrate embryos relies on cilia-driven leftward fluid flow within an LR organizer (LRO). A cardinal question is how leftward flow triggers symmetry breakage. The chemosensation ...

    Abstract Establishment of the left-right (LR, sinistral, dextral) body axis in many vertebrate embryos relies on cilia-driven leftward fluid flow within an LR organizer (LRO). A cardinal question is how leftward flow triggers symmetry breakage. The chemosensation model posits that ciliary flow enriches a signaling molecule on the left side of the LRO that promotes sinistral cell fate. However, the nature of this sinistralizing signal has remained elusive. In the Xenopus LRO, we identified the stem cell growth factor R-Spondin 2 (Rspo2) as a symmetrically expressed, sinistralizing signal. As predicted for a flow-mediated signal, Rspo2 operates downstream of leftward flow but upstream of the asymmetrically expressed gene dand5. Unexpectedly, in LR patterning, Rspo2 acts as an FGF receptor antagonist: Rspo2 via its TSP1 domain binds Fgfr4 and promotes its membrane clearance by Znrf3-mediated endocytosis. Concordantly, we find that at flow-stage, FGF signaling is dextralizing and forms a gradient across the LRO, high on the dextral- and low on the sinistral side. Rspo2 gain- and loss-of function equalize this FGF signaling gradient and sinistralize and dextralize development, respectively. We propose that leftward flow of Rspo2 produces an FGF signaling gradient that governs LR-symmetry breakage.
    MeSH term(s) Animals ; Body Patterning/genetics ; Cilia/metabolism ; Signal Transduction ; Xenopus laevis/metabolism ; Xenopus Proteins/genetics ; Xenopus Proteins/metabolism ; Intercellular Signaling Peptides and Proteins/metabolism
    Chemical Substances Xenopus Proteins ; Rspo2 protein, Xenopus ; Intercellular Signaling Peptides and Proteins
    Language English
    Publishing date 2024-02-02
    Publishing country England
    Document type Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-024-44951-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Book ; Thesis: ANGPTL4 and PTPRK as Wnt negative regulators during early Xenopus development

    Chang, Ling-Shih / Niehrs, Christof

    2018  

    Institution Universität Heidelberg
    Author's details presented by Master of Science Ling-Shih Chang ; referees: Prof. Dr. Christof Niehrs, Prof. Dr. Michael Boutros
    Language English ; German
    Size ii, 125 Blätter, Illustrationen, Diagramme, 30 cm
    Publishing place Heidelberg
    Publishing country Germany
    Document type Book ; Thesis
    Thesis / German Habilitation thesis Dissertation, Ruperto Carola University Heidelberg, Germany, 2018
    Note Text Englisch, Zusammenfassung in deutscher und englischer Sprache
    HBZ-ID HT020994189
    Database Catalogue ZB MED Medicine, Health

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    Shelf markLoan statusLocation
    2021 E 831 order for loan Magazin

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  7. Article ; Online: In Vitro Binding of GADD45A to RNA:DNA Hybrids.

    Arab, Khelifa / Niehrs, Christof

    Methods in molecular biology (Clifton, N.J.)

    2022  Volume 2528, Page(s) 277–287

    Abstract: R-loops are three-stranded RNA:DNA hybrid structures that frequently form during transcription. While R-loop misregulation is associated with genome instability, cells also harness RNA-DNA hybrids in scheduled, "regulatory," R-loops to control gene ... ...

    Abstract R-loops are three-stranded RNA:DNA hybrid structures that frequently form during transcription. While R-loop misregulation is associated with genome instability, cells also harness RNA-DNA hybrids in scheduled, "regulatory," R-loops to control gene expression. One regulatory role involves epigenetic gene regulation by the R-loop reader Growth Arrest and DNA Damage 45A (GADD45A). This small stress related protein promotes DNA demethylation by recruiting TET dioxygenase and Thymine DNA glycosylase to specific genomic loci. GADD45A requires adapters for its genomic localization. One such class of adapters are R-loops formed at certain CpG island promoters to which GADD45A binds directly, targets the demethylation machinery, and confers an open chromatin state. Here, we describe protocols for carrying out in vitro binding assays with GADD45A to RNA:DNA hybrids to biochemically study its direct binding to R-loops, specifically GADD45A pulldown and EMSA (electrophoretic mobility shift) assays.
    MeSH term(s) Cell Cycle Proteins/metabolism ; DNA/chemistry ; DNA/genetics ; DNA Damage ; Genomic Instability ; Humans ; Nuclear Proteins/metabolism ; RNA/chemistry ; RNA/genetics
    Chemical Substances Cell Cycle Proteins ; GADD45A protein, human ; Nuclear Proteins ; RNA (63231-63-0) ; DNA (9007-49-2)
    Language English
    Publishing date 2022-06-15
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-2477-7_18
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  8. Article ; Online: ROTACs leverage signaling-incompetent R-spondin for targeted protein degradation.

    Sun, Rui / Meng, Zibo / Lee, Hyeyoon / Offringa, Rienk / Niehrs, Christof

    Cell chemical biology

    2023  Volume 30, Issue 7, Page(s) 739–752.e8

    Abstract: Proteolysis-targeting chimeras (PROTACs) are an emerging technology for therapeutic intervention, but options to target cell surface proteins and receptors remain limited. Here we introduce ROTACs, bispecific WNT- and BMP-signaling-disabled R-spondin ( ... ...

    Abstract Proteolysis-targeting chimeras (PROTACs) are an emerging technology for therapeutic intervention, but options to target cell surface proteins and receptors remain limited. Here we introduce ROTACs, bispecific WNT- and BMP-signaling-disabled R-spondin (RSPO) chimeras, which leverage the specificity of these stem cell growth factors for ZNRF3/RNF43 E3 transmembrane ligases, to target degradation of transmembrane proteins. As a proof-of-concept, we targeted the immune checkpoint protein, programmed death ligand 1 (PD-L1), a prominent cancer therapeutic target, with a bispecific RSPO2 chimera, R2PD1. The R2PD1 chimeric protein binds to PD-L1 and at picomolar concentration induces its lysosomal degradation. In three melanoma cell lines, R2PD1 induced between 50 and 90% PD-L1 protein degradation. PD-L1 degradation was strictly dependent on ZNRF3/RNF43. Moreover, R2PD1 reactivates cytotoxic T cells and inhibits tumor cell proliferation more potently than Atezolizumab. We suggest that signaling-disabled ROTACs represent a paradigm to target cell surface proteins for degradation in a range of applications.
    MeSH term(s) Receptors, G-Protein-Coupled/metabolism ; Proteolysis ; B7-H1 Antigen/metabolism ; Wnt Signaling Pathway ; Ubiquitin-Protein Ligases/metabolism
    Chemical Substances Receptors, G-Protein-Coupled ; B7-H1 Antigen ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2023-06-14
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2451-9448
    ISSN (online) 2451-9448
    DOI 10.1016/j.chembiol.2023.05.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Uncoupling the BMP receptor antagonist function from the WNT agonist function of R-spondin 2 using the inhibitory peptide dendrimer RW

    Lee, Hyeyoon / Sun, Rui / Niehrs, Christof

    The Journal of biological chemistry

    2022  Volume 298, Issue 2, Page(s) 101586

    Abstract: Signaling by bone morphogenetic proteins (BMPs) plays pivotal roles in embryogenesis, adult tissue homeostasis, and disease. Recent studies revealed that the well-established WNT agonist R-spondin 2 (RSPO2) is also a BMP receptor (BMP receptor type 1A) ... ...

    Abstract Signaling by bone morphogenetic proteins (BMPs) plays pivotal roles in embryogenesis, adult tissue homeostasis, and disease. Recent studies revealed that the well-established WNT agonist R-spondin 2 (RSPO2) is also a BMP receptor (BMP receptor type 1A) antagonist, with roles in early Xenopus embryogenesis and human acute myeloid leukemia (AML). To uncouple the BMP antagonist function from the WNT agonist function and to promote development of AML therapeutics, here we identified a 10-mer peptide (RW) derived from the thrombospondin 1 domain of RSPO2, which specifically prevents binding between RSPO2 and BMP receptor type 1A without altering WNT signaling. We also show that a corresponding RW dendrimer (RW
    MeSH term(s) Adult ; Animals ; Bone Morphogenetic Protein Receptors/antagonists & inhibitors ; Bone Morphogenetic Proteins ; Dendrimers/pharmacology ; Humans ; Intercellular Signaling Peptides and Proteins/metabolism ; Leukemia, Myeloid, Acute ; Peptide Fragments ; Proteins/pharmacology ; Wnt Proteins/agonists ; Wnt Signaling Pathway ; Xenopus laevis
    Chemical Substances Bone Morphogenetic Proteins ; Dendrimers ; Intercellular Signaling Peptides and Proteins ; Peptide Fragments ; Proteins ; Wnt Proteins ; Bone Morphogenetic Protein Receptors (EC 2.7.11.30)
    Language English
    Publishing date 2022-01-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2022.101586
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    Uc I Zs.108: Show issues Location:
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  10. Article ; Online: Regulatory R-loops as facilitators of gene expression and genome stability.

    Niehrs, Christof / Luke, Brian

    Nature reviews. Molecular cell biology

    2020  Volume 21, Issue 3, Page(s) 167–178

    Abstract: R-loops are three-stranded structures that harbour an RNA-DNA hybrid and frequently form during transcription. R-loop misregulation is associated with DNA damage, transcription elongation defects, hyper-recombination and genome instability. In contrast ... ...

    Abstract R-loops are three-stranded structures that harbour an RNA-DNA hybrid and frequently form during transcription. R-loop misregulation is associated with DNA damage, transcription elongation defects, hyper-recombination and genome instability. In contrast to such 'unscheduled' R-loops, evidence is mounting that cells harness the presence of RNA-DNA hybrids in scheduled, 'regulatory' R-loops to promote DNA transactions, including transcription termination and other steps of gene regulation, telomere stability and DNA repair. R-loops formed by cellular RNAs can regulate histone post-translational modification and may be recognized by dedicated reader proteins. The two-faced nature of R-loops implies that their formation, location and timely removal must be tightly regulated. In this Perspective, we discuss the cellular processes that regulatory R-loops modulate, the regulation of R-loops and the potential differences that may exist between regulatory R-loops and unscheduled R-loops.
    MeSH term(s) Animals ; DNA/chemistry ; DNA/genetics ; DNA Damage/genetics ; DNA Damage/physiology ; DNA Repair/genetics ; DNA Replication/genetics ; DNA Replication/physiology ; Gene Expression Regulation/genetics ; Genomic Instability/genetics ; Histone Code/genetics ; Humans ; Nucleic Acid Conformation ; R-Loop Structures/genetics ; R-Loop Structures/physiology ; RNA/chemistry ; RNA/genetics ; Telomere/genetics ; Transcription, Genetic/genetics
    Chemical Substances RNA (63231-63-0) ; DNA (9007-49-2)
    Language English
    Publishing date 2020-01-31
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2031313-5
    ISSN 1471-0080 ; 1471-0072
    ISSN (online) 1471-0080
    ISSN 1471-0072
    DOI 10.1038/s41580-019-0206-3
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