Research
- Research Topics
- Cell Biology and Tumor Biology
- Stem Cells and Cancer
- Inflammatory Stress in Stem Cells
- Experimental Hematology
- Molecular Embryology
- Signal Transduction and Growth Control
- Epigenetics
- Redox Regulation
- Vascular Oncology and Metastasis
- Clinical Neurobiology
- Molecular Neurogenetics
- Molecular Neurobiology
- Mechanisms Regulating Gene Expression
- Molecular Biology of Centrosomes and Cilia
- Dermato-Oncology
- Pediatric Leukemia
- Tumour Metabolism and Microenvironment
- Personalized Medical Oncology
- Molecular Hematology - Oncology
- Cancer Progression and Metastasis
- Translational Surgical Oncology
- Neuronal Signaling and Morphogenesis
- Cell Signaling and Metabolism
- Cell Fate Engineering and Disease Modeling
- Cancer Drug Development
- Cell Morphogenesis and Signal Transduction
- Functional and Structural Genomics
- Molecular Genome Analysis
- Molecular Genetics
- Pediatric Neurooncology
- Cancer Genome Research
- Chromatin Networks
- Functional Genome Analysis
- Theoretical Systems Biology
- Neuroblastoma Genomics
- Signaling and Functional Genomics
- Signal Transduction in Cancer and Metabolism
- RNA-Protein Complexes and Cell Proliferation
- Systems Biology of Signal Transduction
- Areas of Interest
- Advancement of clinical proteomics for systems medicine
- Bridging from the single cell to the cell population – Epo-induced cellular responses and erythroleukemia
- Deciphering tumor microenvironment interactions determining lung cancer development
- Mechanisms controlling the compensation of liver injury and towards model-based biomarkers for early detection of liver cancer
- Application of dynamic pathway modelling for personalized medicine
- Group Members
- Publications
- Open Positions
- Funding
- Teaching
- Areas of Interest
- Molecular thoracic Oncology
- Proteomics of Stem Cells and Cancer
- Computational Genomics and System Genetics
- Applied Functional Genomics
- Applied Bioinformatics
- Translational Medical Oncology
- Metabolic crosstalk in cancer
- Pediatric Glioma Research
- Cancer Epigenomics
- Translational Pediatric Sarcoma Research
- Artificial Intelligence in Oncology
- Mechanisms of Genomic Variation and Data Science
- Neuropathology
- Pediatric Oncology
- Neurooncology
- Somatic Evolution and Early Detection
- Translational Control and Metabolism
- Soft-Tissue Sarcoma
- Precision Sarcoma Research
- Brain Mosaicism and Tumorigenesis
- Mechanisms of Genome Control
- Translational Gastrointestinal Oncology and Preclinical Models
- Translational Lymphoma Research
- Mechanisms of Leukemogenesis
- Genome Instability in Tumors
- Developmental Origins of Pediatric Cancer
- Brain Tumor Translational Targets
- Translational Functional Cancer Genomics
- Regulatory Genomics and Cancer Evolution
- SPRINT
- Cancer Risk Factors and Prevention
- Cancer Epidemiology
- Biostatistics
- Clinical Epidemiology and Aging Research
- Health Economics
- Physical Activity, Prevention and Cancer
- Preventive Oncology
- Personalized Early Detection of Prostate Cancer
- Digital Biomarkers for Oncology
- Tumorigenesis and molecular cancer prevention
- Genomic Epidemiology
- Cancer Survivorship
- Immunology, Infection and Cancer
- Structural Biology of Infection and Immunity
- Cellular Immunology
- B Cell Immunology
- Immune Diversity
- Immunoproteomics
- Personalized Immunotherapy
- mRNA Cancer Immunotherapies
- Tumor Immunology and Tumor Immunotherapy
- Infections and Cancer Epidemiology
- Pathogenesis of Virus-Associated Tumors
- Immunotherapy and Immunoprevention
- Virus-associated Carcinogenesis
- Chronic Inflammation and Cancer
- Microbiome and Cancer
- Molecular Oncology of Gastrointestinal Tumors
- Applied Tumor Immunity
- Neuroimmunology and Brain Tumor Immunology
- Applied Tumor Biology
- Virotherapy
- Adaptive Immunity and Lymphoma
- Dermal Oncoimmunology
- Immune Regulation in Cancer
- Systems Immunology and Single Cell Biology
- Pediatric Immuno-Oncology
- Epithelium Microbiome lnteractions
- Experimental Hepatology, Inflammation and Cancer
- GMP & T Cell Therapy
- Tumorvirus-specific Vaccination Strategies
- Mammalian Cell Cycle Control Mechanisms
- Molecular Therapy of Virus-Associated Cancers
- DNA Vectors
- Episomal-Persistent DNA in Cancer- and Chronic Diseases
- Immune Monitoring
- News
- Imaging and Radiooncology
- Radiology
- Research
- Computational Radiology Research Group
- Contrast Agents In Radiology Research Group
- Neuro-Oncologic Imaging Research Group
- Radiological Early Response Assessment Of Modern Cancer Therapies
- Imaging In Monoclonal Plasma Cell Disorders
- 7 Tesla MRI - Novel Imaging Biomarkers
- Functional Imaging
- Visualization And Forensic Imaging
- PET/MRI
- Dual- and Multienergy CT
- Radiomics Research Group
- Prostate Research Group
- Bone marrow
- Musculoskeletal Imaging
- Microstructural Imaging Research Group
- Staff
- Patients
- Research
- Medical Physics in Radiology
- X-Ray Imaging and Computed Tomography
- Federated Information Systems
- Translational Molecular Imaging
- Medical Physics in Radiation Oncology
- Biomedical Physics in Radiation Oncology
- Intelligent Medical Systems
- Medical Image Computing
- Radiooncology - Radiobiology
- Smart Technologies for Tumor Therapy
- Radiation Oncology
- Molecular Radiooncology
- Nuclear Medicine
- Translational Radiation Oncology
- Translational Radiotheranostics
- Interactive Machine Learning
- Intelligent Systems and Robotics in Urology
- Multiparametric methods for early detection of prostate cancer
- Translational Molecular Imaging in Oncologic Therapy Monitoring
- Radiology
- Cell Biology and Tumor Biology
- Research Groups A-Z
- Junior Research Groups
- Core Facilities
- News
- List of Core Facilities
- Antibodies
- Cellular Tools
- Center for Preclinical Research
- Central Library
- Chemical Biology
- Dieter Morszeck Biorepository
- Electron Microscopy
- Flow Cytometry
- Information Technology ITCF
- Light Microscopy
- Metabolomics
- Microarray
- Microbiological Diagnostics
- Next Generation Sequencing
- Omics IT and Data Management
- Proteomics
- Radiopharmaceuticals and Preclinical Trials
- Single-cell Open Lab
- Small Animal Imaging
- Transgenic Service
- Tumor Models
- OMERO@DKFZ
- List of Technologies
- DKFZ Core Facilities Publication Policy
- Enabling Technology
- Data Science @ DKFZ
- INFORM
- Baden-Württemberg Cancer Registry
- Cooperations & Networks
- National Cooperations
- International Cooperations
- Cooperational Research Program with Israel: DKFZ - MOST in Cancer Research
- Program
- Members of the Program Committee
- Call
- Publication Database
- German-Israeli Cancer Research Schools
- Archive
- Heidelberg - Israel, Science and Culture
- Symposium 40 Years of German-Israeli Cooperation
- 35th Anniversary Symposium
- 34th Meeting of the DKFZ-MOST Program
- 40th Anniversary Publication
- 30th Anniversary Publication
- 20th Anniversary Publication
- Flyer - The Cancer Cooperation Program
- List Publications 1976-2004
- Highlight-Projects
- Cooperational Research Program with Israel: DKFZ - MOST in Cancer Research
- Cooperations with industrial companies
- DKFZ PostDoc Network
- Cross Program Topic RNA@DKFZ
- Cross Program Topic Epigenetics@dkfz
- Cross Program Topic Single Cell Sequencing
- WHO Collaborating Centers
- DKFZ Site Dresden
- Health + Life Science Alliance Heidelberg Mannheim
The role of Rspondins in left-right asymmetry and beyond
![](/__we_thumbs__/91112_1_rspondin.png)
Anti-FGF signaling by Rspo2 establishes a Left-Right FGF signaling gradient in the LR-Organizer.
© dkfz.de
R-Spondins (RSPO1-4) are a family of four secreted proteins implicated in development and cancer, which we have discovered in 2004 as Wnt agonists. RSPOs function by protecting WNT receptors from ubiquitination and degradation by the E3 ubiquitin ligases ZNRF3/RNF43. RSPOs became famous as a key ingredient to maintain organoid cultures where they stimulate stem cell growth. We are investigating the molecular mechanism of RSPO signaling as well as its biological roles during embryonic development. Recently, we found a pivotal role of RSPO2 in development of the Left-Right (LR) body axis.
How animals establish the LR axis, is a fundamental problem in biology, as it serves as the basis for the formation of all subsequent LR-asymmetric structures. LR asymmetry is regulated by the left-right organizer (LRO) where LR symmetry breaking takes place. Defective LRO formation results in heterotaxy (HTX), congenital diseases ranging from organ malformation to misarrangement of organs across the LR axis, notably congenital heart defects. The LRO harbors motile cilia, which rotate clockwise to generate a leftward fluid flow.
We discovered in Xenopus embryos, that rspo2 acts in the LRO as a LR morphogen. Rspo2 is expressed in the LRO and it is necessary and sufficient for organ laterality and LR specification. Specifically, Rspo2 acts as sinistralizing (determining Left-specific cell fate) signal and operates upstream of the well-established Nodal-Pitx2 cassette, which is essential for sinistral fate. Surprisingly, in LR patterning Rspo2 acts as an FGF receptor antagonist. Rspo2 via its TSP1 domain binds Fgfr4 and promotes its membrane clearance by ZNRF3-dependent endocytosis. Concordantly, FGF signaling acts dextralizing (determining Right-specific cell fate) and forms a MAPK signaling gradient across the LRO. This FGF signaling gradient is high on the dextral- and low on the sinistral side. We are currently analyzing the LR signaling cascades downstream of RSPO2 and FGF as well as the evolutionary conservation of this mechanism in mouse.
We recently showed that RSPO2 and RSPO3 are also BMP (bone morphogenetic protein) antagonists. Specifically, RSPO2 is a high affinity ligand for the BMP receptor BMPR1A. RSPO2 forms a ternary complex between BMPR1A and the E3 ligase ZNRF3, which triggers endocytosis and degradation of the BMP receptor. We showed that Rspo2 antagonizes BMP signaling during embryonic axis formation in Xenopus. Moreover, we found that this novel function of RSPO2 as BMP antagonist also plays a critical role in acute myeloid leukemia (AML): AML cells secrete RSPO2 to promote their self-renewal and prevent cell differentiation. RSPO2 expression is generally elevated in AML patients with poor prognosis and inhibiting RSPO2 prolongs survival in AML mouse xenograft models.
Thus, RSPOs are multimodal modulators of growth factor signaling pathways, i.e. they can affect several receptors families (Wnt (ON) – BMP (OFF) – FGF (OFF)). Hence, we suspect even more target pathways and investigate the full repertoire of RSPO target receptors.
References
Lee H, Seidl C, Sun R, Glinka A, Niehrs C. (2020). R-spondins are BMP receptor antagonists in Xenopus early embryonic development. Nat Commun. 11:5570.
Sun R, He L, Lee H, Glinka A, Andresen C, Hübschmann D, Jeremias I, Müller-Decker K, Pabst C, Niehrs C (2021) RSPO2 inhibits BMP signaling to promote self-renewal in acute myeloid leukemia. Cell Rep.36:109559.
Lee H, Camuto CM, Niehrs C. (2024) R-Spondin 2 governs Xenopus left-right body axis formation by establishing an FGF signaling gradient. Nat Commun. 2;15:1003