Overview

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.

Career

Since 2023 Professor of Cell and Developmental Biology (Personal Chair), Biosciences, University of Exeter, UK

2017-2023 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

Links

• The Loop
• ORCID
• Facebook
• LinkedIn
• Research Gate

Research group links

• Cell and Developmental Biology

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Research

Research interests

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 acts 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, reduced cytonemes lead to a restricted ligand distribution 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 (7, 8).

Recently, we demonstrated that cytonemes can deliver fully assembled Wnt ligand/receptor complexes to orchestrated Wnt signalling in the developing zebrafish embryo (9).

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 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 essential 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; (7) Routledge et al., eLife, 2022; (8) Rogers et al., P.N.A.S., 2023; (9) Zhang et al., Nature, 2024

Research projects

OPEN POSITIONS:

We're recruiting talented graduates from all areas of bioscience to become MSc students, PhD students and postdoctoral researchers in our lab. Contact us to talk about possibilities. 

Join our team!

Research grants

• 2022 BBSRC
  Establishing precise genome editing in zebrafish and its application to advance understanding of the Wnt/PCP signalling pathway
• 2022 BBSRC
  BBSRC Responsive Mode, BB/W015420/1
• 2021 MRC
  MRC Confidence in Concept (CiC) Project with AstraZeneca
• 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

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External Engagement and Impact

Administrative responsibilities

• Chair of the LSI Lab Management Group (LMG)
• Deputy Director of Postgraduate Research (D-DPGR)

Committee/panel activities

• Panel member of the BBSRC committee C (since 2022)
• Panel member of the Polish RC committee, National Science Centre, Poland (since 2019)

Editorial responsibilities

• Scientific editor of Mechanisms of Development (MOD) (2016 - present)
• Scientific editor of Genesis, John Wiley and Sons, Inc (2015 - present)
• Associated editor of Frontiers in Neuroscience (2011 - present)

External doctoral examining nationally and internationally

• PhD       Maastricht, The Netherlands; Supervisor Dr Stefan Giiselbrecht, 2022
• PhD       Francis Crick, UK; Supervisor Prof Jim Smith, 2021
• PhD       iBV, Nice U, France; Supervisor Dr M. Fürthauer, 2021
• PhD       U Nottingham, UK; Supervisor Prof Martin Gehring, 2019
• PhD       Oxford Brookes U., UK; Supervisor Prof Alistair McGregor, 2019
• MPhil     U Bristol, UK; Supervisor Dr Beck Richardson, 2018

Invited lectures

Number of invited lectures in total	International lectures	National lectures
over 60	over 40	over 20

Workshops/Conferences organised

2022                Organizer, EMBO workshop on "Long-distance cell-cell communication", Exeter, UK.

2020                Organizer, Southwest Zebrafish Meeting 2020, Exeter, UK.

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.

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Teaching

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.

Modules

2023/24

• BIO2088 - Advanced Cell Biology

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Supervision / Group

Postdoctoral researchers

Postgraduate researchers

Research Technicians

Alumni

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