Dr Steffen Scholpp
Associate Professor, Cell and Developmental Biology
+44 (0)1392 727451
Living Systems Institute T02.12
Living Systems Institute, University of Exeter, Stocker Road, Exeter, EX4 4QD
Tissue development is a key process for life starting from the earliest embryonic stages during which cells differentiate into later organs composing an entire body. An essential component for these developmental processes but also for tissue regeneration and stem cell regulation is the communication of cells by chemical signalling. The highly conserved family of Wnt proteins represents important regulators of cell behaviour, tissue development and homeostasis by inducing responses in a concentration-dependent manner. We identified a novel way of spreading Wnt proteins in vertebrates: Wnt molecules are mobilized on specific cell protrusions known as cytonemes. These specialized signalling filopodia transmit signal proteins between communicating cells and allow a high degree of control of propagation speed, direction and concentration of the transmitted ligand. The signalling molecules are delivered directly to the receiving cells by a direct-contact model and parameters such as cytoneme length or speed of filopodia formation dictate local Wnt concentration.
In our research, we use the zebrafish embryo to investigate how intercellular Wnt protein transport is regulated and how signals are subsequently delivered to the target cell in a living vertebrate organism. By understanding Wnt dissemination mechanisms, we will be able to control Wnt signalling in development, and regeneration. This research is funded by the Biotechnology and Biological Sciences Research Council (BBSRC).
We further use gastric cancer cells to investigate how cytonemes mobilize Wnts in tumour tissue. Our research will open up new strategies to control Wnt signalling by altering its transport route in the tumour microenvironment. Our research is supported by the Medical Research Council (MRC).
At the Living Systems Institute, we collaborate with biophysicists using super-resolution microscopy to describe these signalling processes in a quantitative way on a molecular level. As it is very difficult to determine the specific impact of individual parameters in a complex biological system by a purely experimental approach, we interact with mathematicians using computational modelling. Together, we develop a robust mathematical model for the distribution of signal molecules on the basis of signalling filopodia. Due to the conserved nature of vertebrate cell behaviour, our results will be relevant to Wnt signalling during human embryonic development and could suggest novel vulnerabilities to Wnt-dependent diseases – a prerequisite for the development of novel therapeutics.
2009-2016 Emmy-Noether Research Group Leader (Assistant Professor)
2003 PhD Neurobiology (Hons., summa cum laude), University of Heidelberg, Germany
2017-present Associate Professor of Cell and Developmental Biology, Biosciences, University of Exeter, UK
2009-2016 Emmy-Noether group leader (Assistant Professor) at the Karlsruhe Institute of Technology (KIT), Germany
2004-2009 Postdoctoral Research Fellow with Prof Andrew Lumsden, FRS, MRC Centre for Developmental Neurobiology, King’s College London, UK
2003-2004 Postdoctoral Research Associate with Prof Michael Brand, Max Planck-Institute of Cell Biology and Genetics (MPI-CBG), Dresden, Germany
2003 PhD Neurobiology (Hons., summa cum laude), University of Heidelberg, Germany
1999-2003 PhD student in Neurobiology (Laboratory of Prof Michael Brand), University of Heidelberg, Germany and Max Planck-Institute of Cell Biology and Genetics (MPI-CBG), Dresden, Germany
Wnt protein (red) on cytoneme tips in vivo
After secretion, developmental signals known as morphogens must travel relatively long distances to form a concentration gradient that the responding tissue uses to acquire positional information. The role of morphogen transport and endocytic trafficking in this process is the subject of intense debate. Wnt proteins regulate developmental processes, tissue regeneration and stem cell maintenance. It has been postulated that Wnt/β-catenin signalling forms concentration gradients across responsive tissues and act as morphogens. However, little is known about the transport mechanism for these lipid-modified signalling proteins in vertebrates.
Recently, we showed that Wnt8a is transported on short, actin-based filopodia known as cytonemes to contact responding cells and activate signalling during neural plate formation in zebrafish (1).Wnt/ Ror2 signalling regulates the formation of these Wnt cytonemes (5). Enhanced formation of cytonemes increases the effective signalling range of Wnt by facilitating spreading. Consistently, reduction in cytonemes leads to a restricted distribution of the ligand and a limited signalling range. Using a numerical simulation, we provide evidence that such a short-range transport system for Wnt has a long-range signalling function.
We also showed that Wnt cytonemes are essential to disseminate Wnt signalling in gastric tumours. In this tissue, fibroblasts produce Wnts and distribute them via a dynamic cytoneme network within the cancer tissue to regulate proliferation and metastasis.
After contact by Wnt/β-catenin positive filopodia, a multi-protein complex at the plasma membrane assembles clustering membrane-bound receptors and intracellular signal transducers into the so-called Lrp6-signalosome. Our imaging studies in live zebrafish embryos showed that the signalosome is a highly dynamic structure, which is continuously assembled and disassembled by a Dvl2-mediated endocytic process (2). We showed that this endocytic process is not only essential for ligand-receptor internalization but also for signalling.
We conclude that a cytoneme-based transport system for Wnt and subsequent endocytosis is important for Wnt/β-catenin signalling in development and disease (3,4,6).
(1) Stanganello et al., Nature Comms., 2015; (2) Hagemann, et al., J.Cell Sci., 2014; (3) Zhang and Scholpp, 2019; (4) Brunt and Scholpp, CMLS, 2017; (5) Mattes et al., eLife, 2018. (6) Brunt et al., Nat Comms 2021
We're recruiting talented graduates from all areas of bioscience to become MSc students, PhD students and postdoctoral researchers in our lab.
- LSI-funded PhD student position, start Sep 2022
Molecular analysis of the Wnt receptor presentation during stem cell fate transition.
Supervisor team: Steffen Scholpp, Austin Smith, Fabrice Gielen, Kyle Wedgwood
Disciplines: Cell and developmental biology, molecular biology, microfluidics, biomathematics
Paracrine signals orchestrate the acquisition of cellular fate in the developing embryo. Early cell fate decisions in the neural ectoderm are based on the 'Activation-Transformation Model' postulated from Nieuwkoop in 1952: in the first phase, a signal induces a pool of neural stem cells, while in the second phase a signal transforms the posterior located stem cells into neural progenitor cells of caudal fates such as hindbrain cells. Studies in fish, frog and mouse demonstrated that the signal inducing hindbrain fate belongs to the Wnt/beta-catenin signalling family, namely Wnt8a. Wnt8a is produced at the embryonic margin and forms a morphogen gradient in the neural plate. Neural stem cells located close to the Wnt8a positive margin acquire hindbrain fate.
Recent work from our lab has shown that Wnt8a is loaded on signalling filopodia known as cytonemes. Cytonemes are required to transport Wnt8a from the margin cells to the prospective hindbrain progenitor. Consistently, blockage of cytoneme formation leads to a strongly reduced hindbrain primordium. Upon contact with the Wnt cytoneme, the gene regulatory network (GRN) of the neural stem cell collapses, and the GRN of the hindbrain progenitor is initiated: neuronal stem cells express key transcription factors such as Otx2 and upon Wnt activation, they switch from Otx2 expressing cells to cells expressing hindbrain-specific transcription factors such as Gbx1. In a second phase, Wnt/beta-catenin signalling regulates the transition of these Gbx1-positive neuronal progenitors to fully functional neurons in the hindbrain.
Many steps of the differentiation process of stem cells to fully functional neurons are controlled by Wnts, including self-renewal and cell differentiation. Fine temporal control of the activity of this crucial signalling pathway is required to allow a precise sequence of differentiation events. However, it is still unclear how receptors, transducers and effectors of the Wnt signalling pathway are regulated during cell fate transition.
In this project, we will quantify Wnt regulators during hindbrain specification in zebrafish. As an alternative strategy, we will use mouse embryonic stem cells (mESC) as a well-studied and controllable system. We will measure the concentration of Wnt receptors, co-receptors, scaffolding proteins at the plasma membrane during different stages of the Wnt-mediated cell fate transition. To do so, we will co-cultivate Wnt8a expressing cells with Gbx1-GFP reporter cells from zebrafish in several thousand microdroplets for a defined duration. We will image the dynamic process of formation of Wnt-bearing cytonemes in the microdroplet. Successful transport and signal activation will be monitored by measuring the induction of Gbx1 expression by an increase of GFP fluorescence in the receiving cell. Alternatively, we will co-cultivate the mESC with microspheres coated with a defined concentration of Wnt protein. At different time points, we will use and adapt a recently developed high-throughput droplet sorter to isolate the receiving cells and subject them to a surface biotinylation analysis. In the following biotinylation analysis, we will label cell surface proteins with a biotin reagent before lysing the cells and isolating the tagged proteins by pull-down by NeutrAvidin beads for subsequent mass spectrometry (MS) analysis. As a contingency plan, we will subject the samples to SDS-PAGE separation and probed with specific antibodies. Quantification of cell surface expression will be accomplished by densitometric measurement of the bands corresponding to the protein of interest. In collaboration with mathematicians, we will use the acquired data to establish a computational model for cell fate transition based on cytoneme-mediated signal activation.
By the end of this project, we will have established a complete picture of the dynamic presentation of Wnt receptors, co-receptors and modifiers during Wnt activation. This information will provide new fundamental knowledge of Wnt-regulated cell fate transition in a vertebrate organism. We believe that these findings will have a significant impact on basic cell and developmental biology and result in a deeper understanding of cytoneme-based cell communication and tissue development. In this way, we aim to control the spatiotemporal activation dynamics of Wnt signalling networks in a vertebrate tissue. We envisage that the results will therefore serve as a basis for the development of novel tools to manipulate Wnt signalling pathways during development, regeneration, and for treatment of human disease.
Under the supervision of cell biologists and biophysicist, the student will experimentally monitor cytoneme-based Wnt transport and cell differentiation. The student will use state-of-the-art microfluidics to control cell-cell communication events at the single-cell level. The student will use imaging-based, quantitative measurements of interactions and simultaneously describe signalling activation in the receiving tissue by using real-time PCR, single-molecule fluorescence in-situ hybridisation, and advanced microscopy. Under the guidance of simulation experts, the student will test the findings and validate predictions in a stochastic, dynamic model.
The student selected for this project will develop invaluable skill sets in experimental genetics, microfluidics, nanotechnology, microscopy and mathematical modelling, whilst also making a significant contribution to the understanding of signalling biology. This combined skill set will make the candidate a highly desirable recruitment prospect for future academic and industrial employers.
- CSC-funded PhD student position, start Sep 2021
Locally delivered Wnt signal orchestrate cell fate acquisition in stem cells.
Supervisor team: Steffen Scholpp, Michael Schrader, Christian Soeller, Kyle Wedgwood
Disciplines: Cell and developmental biology, molecular biology, microfluidics, biomathematics
The evolution and development of multi-cellular organisms are dependent on mechanisms which facilitate inter- and intracellular communication. These mechanisms are fundamental to our understanding of embryogenesis, tissue homeostasis, wound healing and regeneration. Inter- and intracellular communication involves bidirectional signalling across membranes. This information exchange is achieved by striking a delicate balance between restriction and propagation of information over different scales of time and space.
Our studies demonstrate that cells send out signalling filopodia to facilitate communication between cells. In addition, we have shown that there is also extensive communication between cell organelles highlighting a surprisingly intensive intracellular communication network. In this network, we want to understand the underlying general principals of communication across membranes, which give rise to a multitude of context-dependent signalling responses.
Stem cell differentiation involves the changing of a cell to a more specialized cell type, involving a switch from proliferation to specialization. The mechanism controlling asymmetric division and differentiation of stem cells is only partially understood. Signalling filopodia are also known as cytonemes regulate trafficking of Wnt proteins between cells. At the single-cell level, Wnt cytonemes contact specific sites on the plasma membrane of the receiving cells to control cell differentiation and proliferation. Preliminary data suggest that cytonemes can induce the asymmetric distribution of Wnt/beta-catenin signalling components and directed asymmetric inheritance cellular components in stem cells. The cytoneme-contacted daughter cell shows elevated levels of Wnt/beta-catenin and expresses markers of pluripotency, whereas the daughter cell - without cytonemal contact - switches from proliferation to specialization.
- MSc/MbRes student position, start Jan 2022
Functional analysis of Wnt signalling on peroxisome formation in zebrafish development
Supervisor team: Steffen Scholpp, Michael Schrader
Join our team!
- 2020 BBSRC
Lattice-based Microscopy to analyse subcellular dynamics in living specimen;: BBSRC 19-ALERT Mid-range equipment initiative; 2020-2021; BB/T017899/1
- 2019 Medical Research Council
Deciphering the molecular mechanism of Wnt trafficking in gastric cancer; MRC Research Grant; 2019-2022; MR/S007970/1
- 2019 BBSRC
Quantitative analysis of cytoneme-based Wnt trafficking and signalling in vivo; BBSRC Responsive Mode; 2019-2022; BB/S016295/1
- 2019 BBSRC
HPF to enable a high-quality ultrastructural analysis of biological samples; BBSRC 18-ALERT Mid-range equipment initative; 2019-2020; BB/R019499/1
- 2018 BBSRC
A Single Molecule Detection Unit to perform in vivo FCS and FLIM-FRET analysis in zebrafish; BBSRC 17-ALERT Mid-range equipment initiative; 2018-2019; BB/R013764/1
- 2017 Wellcome Trust
CBMA Seed Corn Award, 2018; WT105618MA
Publications by category
Publications by year
Steffen_Scholpp Details from cache as at 2021-08-01 05:30:33
External Engagement and Impact
- Chair of the LSI Lab Management Group (LMG)
- Deputy Director of Postgraduate Research (D-DPGR)
- Co-organiser of the Biosciences Seminar Series
- Member of the reviewer panel for the OPUS, National Science Centre, NSC (2019)
- Reviewer for the Royal Society (2018 - present)
- Reviewer for the Medical Research Council, MRC (2017 - present)
- Reviewer for Biotechnology and Biological Sciences Research Council (BBSRC) (2016 - present)
- Reviewer for the National Science Centre, NSC Poland (2014 - present)
- Reviewer for the German Research Council (DFG) Germany (2010 - present)
- Scientific reviewer for DFG-Center for Regenerative Therapies, Dresden (CRTD) (2010)
- Scientific editor of Mechanisms of Development (MOD) (2016 - present)
- Scientific editor of Genesis, John Wiley and Sons, Inc (2015 - present)
- Scientific editor of Molecular Science, AIMS Press (2014 - present)
- Associated editor of Frontiers in Neuroscience (2011 - present)
External doctoral examining nationally and internationally
- PhD Francis Crick, UK Supervisor Prof Jim Smith 2021
- PhD iBV, Nice U, FR Supervisor Dr M. Fürthauer 2021
- PhD U Nottingham Supervisor Prof Martin Gehring, 2019
- PhD Oxford Brookes U. Supervisor Prof Alistair McGregor 2019
- MPhil U Bristol Supervisor Dr Beck Richardson 2018
Internal doctoral examining responsibilities
- PhD UoE Supervisor Prof Christian Soeller 2021
- PhD UoE Supervisor Prof Michael Schrader 2018
- PhD UoE Supervisor Dr Tetsu Kudoh 2018
- MPhil UoE Supervisor Dr Matt Winter 2017
Selected activities as referee for scientific journals
eLife; Nature Communications; PLoS Biology; PNAS; EMBO reports; J Cell Sci; Development; Stem Cell Reports; Scientific Reports; Developmental Biology; Brain Structure & Function; Neurobiology of Disease; Neural Development; PLoS One; Differentiation; J of Medical Genetics; Cell & Tissue Research; Genesis; Cellular and Molecular Life Science; Development, Genes & Evolution
2016-2017 elected member of the KIT convent
2013 - 2014 Coordinator of the research cluster “Neural development and neural stem cells” of the Helmholtz Research Program “BioInterfaces”
2012 - 2013 Spokesman of the Young Investigator Network (YIN); assembly of junior faculties at
2010 - 2016 Member of the PhD Selection Committee for the BioInterfaces Graduate School, KIT
since 2010 Post-Graduate Student Advisor, KIT
2009 - 2011 Organizer of the Internal Seminar Series “On Fish and Technologies”, ITG, KIT
2009 - 2016 Member of the Faculty of Chemistry and Life Science, KIT, Germany
Number of invited lectures in total
Recently invited lectures
- Centre of Developmental Neurobiology, King's College London
- U Nottingham
- U Heidelberg
- SignaLIFE, Nice
- 8th Strategic Conference of Zebrafish Investigators, Asilomar, San Francisco, US
- NUS Singapore
- University of Warsaw, Poland
- University of Aberdeen
- University of Bristol
- University of Warwick
- University of Manchester
- University of Sheffield.
- Duke-NUS, Singapore
- University of Calgary, Canada
- ARUK Oxford
- University of Madrid, Spain
- University of Exeter UK
- University of Bath, UK
- EZPM Lisbon, Portugal
- EMBO Wnt meeting, Brno, Czech Republic
- UCSF, San Francisco, USA
- Uni Jena, Germany
- Dev. Biol. Soc. Meeting, Nuremberg, Germany
- ETH Zürich Switzerland
- EMBO workshop, Madrid, Spain
- Gordon Research Conference on Developmental Biology, Mount Holyoke College, USA
- DanStem Center, Copenhagen
- Instituto de Neurociencias, Alicante, Spain.
2019 - Fellow of the Royal Society of Biology
2011 – 2015 Member of the DFG Research Network 1036: “Mechanism, functions and evolution of Wnt signalling pathways”
2007 Honorary Member of the Royal Microscopical Society (RMS)
2020 Organizer, Southwest Zebrafish Meeting 2020, Exeter, UK.
2015 Session Chair, EMBO workshop „Signaling synapsis“, Madrid, Spain.
2014 Session Chair, European Zebrafish PI Meeting, Ein Gedi, Israel.
2013 Organizer, EMBO practical course „Imaging of Neural Development“, KIT, Germany.
Lecturer, Summer School, Jap Soc Dev Biol, Tokyo, Japan.
2012 Lecturer, GfE Summer School, Schloss Reissenburg, Ulm, Germany.
Session Chair, SURF Meeting Biozentrum Basel, Switzerland.
2011 Session Chair, Regional Meeting on Fish Genetics and Development, Landeck, Germany.
2002 Instructor, EMBO Developmental Biology Practical Course, MPI Tübingen, Germany.
Happy Lab Citizen
I have taught at the undergraduate and graduate level, including general biology, cell biology, developmental biology, and neurobiology at the Karlsruhe Institute of Technology and the University of Exeter. I have also personally trained over 20 undergraduates in research, some of whom have been my co-authors on peer-reviewed publications.
Teaching is a privilege, and so I try to practice teaching the most effective way to optimize student learning. I enjoy training students to learn science by doing science, both in terms of hands-on research activities and courses that emphasize formulating research questions, critical analysis of data, and drawing meaningful conclusions. My goal is to teach the subject matter, but also to teach students how to train themselves to learn. As module coordinator, I emphasize organization and context while being mindful of how different students learn and what techniques work best both inside and outside of contact hours, in the classroom or the lab.
I have received several teaching awards at the Karlsruhe Institute of Technology, including the German Certificate for Higher Education (Baden-Württemberg Zertifikat fur Hochschuldidaktik, 200h) in 2012. In 2013, I was awarded the Certificate for Academic Leadership (3y, 160h) to guide working groups in an efficient and target-orientated way.
Current Teaching Activities
BIO2088 Advanced Cell Biology (Module coordinator)
BIOM528 Advanced Topics in Biological Sciences
BIO3911 Professional Development Experience
BIO1333 Fundamental Principles for Bioscientists Year 1 Academic Tutorials
BIO2071 Research Skills and Bioethics Year 2 Academic Tutorials
BIO3077 Year 3 Academic Tutorials
BIO2096 Biosciences Research Projects
Former Teaching Activities
2013 - 2016 Lecturer of the International Zebrafish and Medaka course (IZMC) at the EZRC
2010 - 2016 Lecturer of Biointerface International Graduate School (BIF-IGS)
2010 - 2016 Lecturer and supervisor in BSc and MSc program “Life Science” at the Faculty of Chemistry and Life Science; 1 lecture series per semester, supervision for 2 practical courses per semester
The Scholpp lab in 2020
Supervision / Group
- Lucy Brunt
- Yosuke Ono
- Sally Rogers
- Michael Dawes (BBSRC DTP Student)
- Joshua Donnelly
- Kevin Fang (Chinese Scholarship Council, CSC, Student)
- Daniel Routledge (MRC DTP Student)
- Gemma Sutton (BBSRC DTP Student)
- Chengting Zhang (Chinese Scholarship Council, CSC, Student)
- Holly Elson
- Agnieszka Kaczmar
- Bernadett Boesze PhD student (2012-2016)
- Simone Geyer PhD student(2012-2015)
- Anja Hagemann PostDoc (2009-2014)
- Benjamin Mattes PhD student (2015-2018)
- Daniela Peukert PhD student(2008-2011)
- Lauren Porter MSc student(2018-2019)
- Charanya Rengarajan PhD student (2009-2013)
- Simone Schindler Technician (2017-2018)
- Eliana Stanganello PhD student, summa cum laude (2011-2015)
- Joana Viana PostDoc (2018-2019)