Professor David Strutt

david.jpg

Professor of Developmental Genetics
Wellcome Trust Senior Fellow in Basic Biomedical Science
Director of Research
Department of Biomedical Science
The University of Sheffield
Western Bank, Sheffield S10 2TN
United Kingdom

Room: D36 Firth Court
Telephone: +44 (0) 114 222 2372
Email: d.strutt@sheffield.ac.uk

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General

Brief career history

  • 2005: Professor of Developmental Genetics
  • 2003-present: Wellcome Senior Fellow in Basic Biomedical Science, University of Sheffield
  • 1998-2003: Lister Institute-Jenner Research Fellow, University of Sheffield
  • 1997-1998: Lecturer, University of Sheffield
  • 1993-1997: Postdoctoral Fellow, European Molecular Biology Laboratory, Heidelberg
  • 1991-1993: Postdoctoral Fellow, Department of Anatomy, University of Cambridge
  • 1988-1991: PhD, Department of Anatomy, University of Cambridge
  • 1985-1988: BA Natural Sciences, University of Cambridge

Research interests

We are interested in the genetic control of animal development and how cells interact to build complex tissues and organs. We focus on the particular problem of how cells coordinate their polarity within developing tissues, and as a model study the phenomenon of planar polarity in epithelia of the fruitfly Drosophila

Professional activities

  • Scientific Director, The Bateson Centre
  • Member of Human Frontiers Science Program Grants Committee (2013-2017)
  • Visiting scientist Kavli Institute for Theoretical Physics (KITP), University of California, Santa Barbara (August 2013, August 2016)
  • Editorial boards of “Current Biology” and “Development”
  • Member of “British Society for Developmental Biology” and “The Genetics Society”
  • Lister-Jenner Fellow 1998-2003

Full publications

Research

Understanding mechanisms of coordinated cell polarisation during animal development

Lay summary of research

We are interested in the process of morphogenesis, which is the process by which a body grows and develops to form complex tissues and organ systems. This involves the regulation and coordination of three processes: first, the multiplication of cells; second, the differentiation of the right types of cells in the right positions; third, the correct orientation of cells relative to each other. It is this final process in which we are primarily interested.

As the orientation of cells relative to each other is a fundamental conserved process in animal development, we are able to study it using model experimental systems, in particular the fruitfly Drosophila melanogaster. Using this organism we can easily manipulate the function of genes, which has allowed the identification of a large number of genes that are involved in the coordination of cell orientation.

The aims of our research are to understand how these genes work together and how they are organised into hierarchies. By understanding how the genes act, we hope to be able to intervene to correct developmental diseases caused by dysfunction of the genes, and also gain insights into conditions such as cancer metastasis which involve coordinated changes in cell polarity.

Scientific summary of research

Morphogenesis – the formation of multidimensional structures from cells and groups of cells – is one of the fundamental processes underlying the development of complex multicellular organisms. A key property underlying many morphogenetic processes is the ability of cells to coordinate their polarity within a sheet of cells, a phenomenon referred to as "planar polarity" or "planar cell polarity [PCP]". Planar polarity enables the concerted cell movements and rearrangements necessary to shape tissues, and allows the production of arrays of polarised structures such as hairs and cilia.

Work in the Strutt lab seeks to understand molecular mechanisms of planar polarisation. Our approach is to study two conserved mechanisms, the "core" Frizzled-dependent planar polarity pathway and the Fat/Dachsous pathway. Our goal is to dissect the feedback and cell-cell communication mechanisms that mediate coordinated cellular symmetry breaking, and ask how this can be aligned with the axes of tissues.

We exploit the traditional strengths of molecular genetic analysis in Drosophila to precisely manipulate gene and protein function in vivo, taking advantage of the minimal genetic redundancy and the easy accessibility of developing tissues. In particular, this system allows us to perform in vivo cell biology, analysing protein dynamics and behaviour in the context of developing tissues. To do this, we employ both conventional high resolution in vivo imaging techniques such as confocal microscopy, methodologies such as FRAP (fluorescence recovery after photobleaching) and also super-resolution microscopy. These in vivo studies of protein behaviour are combined with studies of the biochemical interactions of pathway components, targeted genetic screens to identify novel regulatory factors, and computational modelling.

Our long term goal is a fundamental understanding of how coordinated cell polarisation is achieved through the integrated spatiotemporal interactions of pathway components acting from the molecular (nanometer) to cellular (micrometre) to tissue (millimetre) scales.

Figure 1

Examples of planar polarised structures on the adult cuticle of the fruitfly Drosophila. Top: photomicrograph of an adult wing (left) with inset (right) showing the regular array of planar polarised hairs on the surface of the wing. Bottom: Scanning electron micrograph of an adult eye (left) with inset (right) showing a histologically stained microtome section through the eye revealing the regular planar polarised arrangements of the groups of cells within the eye that form each facet.

Figure 2

Funding

  • Wellcome Trust Senior Fellow in Basic Biomedical Science (2003-)
Teaching

Undergraduate and postgraduate taught modules

Level 2:

  • BMS237 Advanced Developmental Biology
Opportunities

Postgraduate PhD studentship opportunities

Mechanisms of cell signalling and coordination of cell polarity in animal development

Tissue morphogenesis, repair and regeneration requires cells to communicate and coordinate their behaviours. Major pathways involved are the Wnt/Frizzled and Fat/Dachsous planar polarity pathways that mediate polarised cell signalling in epithelia sheets. Loss of their activity leads to a variety of developmental abnormalities in animal models such as failure of neural tube closure, cleft palates and heart defects, as well as deficits in wound healing and failure to repair kidney damage resulting in polycystic tubules, and is also implicated in cancer metastasis.

The project will focus on understanding molecular mechanisms of Wnt/Frizzled and Fat/Dachsous pathway activity, and in particular how individual proteins adopt polarised distributions with cells, and the signalling mechanisms that propagate this polarity from cell to cell. A molecular genetic approach will be used, taking advantage of the well-established model Drosophila, which provides sophisticated molecular and genetic and cell biological tools. A major focus in the lab is understanding protein dynamics during cell signalling, using techniques such as live imaging (both conventional and super-resolution) and FRAP, and combining this with genetic screens to identify new pathway components and cell biology and biochemical studies of protein behaviours. We combine these experimental studies with computation modelling approaches to aid in experimental design and hypothesis testing.

References

  • Hale, R., Brittle, A.L., Fisher, K.H., Monk, N.A. and Strutt, D. (2015) Cellular interpretation of the long-range gradient of Four-jointed activity in the Drosophila wing. eLife 4, e05789. [PMC4338440]
  • Strutt, H.*, Searle, E.*, Thomas-MacArthur, V., Brookfield, R. and Strutt, D. (2013) A Cul-3-BTB ubiquitylation pathway regulates junctional levels and asymmetry of core planar polarity proteins. Development 140: 1693-1702. [PMC3621487]
  • Brittle, A., Thomas, C. and Strutt, D. (2012) Planar polarity specification through the asymmetric subcellular localisation of the atypical cadherins Fat and Dachsous. Current Biology 22: 907-914. [PMC3362735]
  • Strutt, H.*, Warrington, S.J.* and Strutt, D. (2011) Dynamics of core planar polarity protein turnover and stable assembly into discrete membrane subdomains. Developmental Cell 20: 511-525. [PMC3094756]

Keywords: Biochemistry, Cancer / Oncology, Cell Biology / Development, Genetics

For informal enquiries about this project, please contact:


Epithelial morphogenesis: coordinating planar polarity and tissue mechanics

Co-Supervisor: Dr Alex Fletcher (Mathematics and Statistics)

As an organism develops, tissues are shaped and patterned in a coordinated way. The long-standing dogma of developmental biology is that secreted proteins diffuse to form expression gradients throughout tissues thereby providing spatial cues to direct growth, fate and pattern, drawing responses from cells even at some distance from the source. More recently, studies have revealed critical roles for mechanical forces in regulating morphogenesis, however, the interplay between these two systems is poorly understood. With the advent of fast 4D live imaging, combined with genetically encoded fluorescent sensors and sophisticated computational modelling tools, is it now possible to make major advances in understanding epithelial tissue dynamics at a quantitative systems level.

The model organism Drosophila provides an ideal system for dissecting mechanisms of morphogenesis in cell sheets, as it is highly amenable to genetic manipulation and has easily accessible simple tissues suitable for live imaging. The project will integrate cutting-edge genetic tools, advanced 4D fast live imaging and computational modelling in an iterative manner to: (i) explore how mechanical forces influence patterning and polarity; (ii) understand how cell division modulates tissue mechanics and coordinated cell polarity; and (iii) develop mathematical approaches to incorporate pattern and proliferation within existing modelling frameworks for epithelial morphogenesis.

We are looking for an enthusiastic and ambitious student to carry out this interdisciplinary project using both experimental and computational approaches. This project will be suitable for a student with a strong quantitative background (e.g. mathematics, physics, engineering or computer science) who is keen to apply their skills to a biological problem with potentially significant translational importance, or a student with a biological background but a strong interest and some skills in computational approaches. Moreover, the student will be provided with an interdisciplinary training, gaining valuable laboratory experience, particularly in high-level imaging and image analysis, as well as in mathematics and computational modelling.

References

  • Warrington SJ, Strutt H and Strutt D. (2013) The Frizzled-dependent planar polarity pathway locally promotes E-cadherin turnover via recruitment of RhoGEF2. Development 140(5):1045-1054.
  • Strutt H*, Warrington, SJ* and Strutt D. (2011) Dynamics of core planar polarity protein turnover and stable assembly into discrete membrane subdomains. Developmental Cell 20: 511-525.
  • Kursawe J, Brodskiy PA, Zartman JJ, Baker RE, Fletcher AG. Capabilities and Limitations of Tissue Size Control Through Passive Mechanical Forces. PLoS Comput Biol. 2015 Dec 29;11(12):e1004679.
  • Tetley RJ, Blanchard GB, Fletcher AG, Adams RJ, Sanson B. Unipolar distributions of junctional Myosin II identify cell stripe boundaries that drive cell intercalation throughout Drosophila axis extension. eLife. 2016 May 16;5:e12094.

For informal enquiries about this project, please contact:

For further information about these projects and how to apply, see our PhD Opportunities page:

PhD Opportunities

Selected publications