Background and scientific rationale
Embryonic tissues and organs are shaped and patterned by complex genetic, molecular and cellular mechanisms that regulate essential processes during development . Dissecting such mechanisms remains challenging as the formation of tissues is controlled on different levels including genes that regulate cell-fate decisions, biochemical signalling pathways and mechanical (physical) forces that act within and between cells to define 3D form and function. Our group aims to understand how these complex processes on multiple scales are linked using the zebrafish embryo as a model system – from tissue to cells, from the cell membrane to the nucleus, and on transcriptional/genomic level. This requires an interdisciplinary approach where we combine approaches from molecular and cell biology, advanced microscopy, genetics, biophysics tools, computational image analysis, transcriptomics and theoretical modelling.
In particular, the lab is interested in processes during development that require mechanical (physical) forces such as cell movements, cell divisions, cell shape changes, cell adhesion and cell specification . It is now well recognised that cells for example push and pull on each other and thereby triggering profound changes in cell and tissue behaviour that are essential to drive many developmental programmes . However, the precise mechanisms involved are not well explored. We aim to understand how forces drive cell and tissue morphogenesis (how do tissues get their shape?), cell migration (how do cells move directionally?), cell-cell adhesion (how do cells physically communicate?) and cell fate specification (how do cells change their identity?).
Below are examples of potential projects available that highlight the broad scope of topics and technologies the lab:
- Feedback between cell fate specification and tissue morphogenesis. This project investigates how progenitor cells organise into different territories and establish boundaries during tissue formation in the early embryo . Objective – Unravelling how cellular and tissue dynamics contribute to establishing different territories with distinct cell fates. Methods – Live imaging of zebrafish embryos, quantitative image analysis of cellular morphodynamics (movement, shape) and molecules involved in cell fate specification (transcription factors, morphogens). Biophysical characterisation of cells in vitro.
- Force sensing and response via cell-cell mechanotransduction. Mechanical stimuli can have a range of effects on embryonic stem cell (ES) behaviour . Yet, it is unclear how cells respond to specific force inputs (type, magnitude) transmitted through cell-cell adhesions. Objective - Identifying how ES cells sense and respond to distinct mechanical signals (e.g. pushing vs pulling). Methods - Microfluidics (capturing cells and force application), live cell imaging using light sheet microscopy, computational analysis of cell and molecule dynamics. Transcriptomics and bioinformatics.
- Recapitulate early brain development in vitro. Recent stem cell models (gastruloids, organoids) highlight the remarkable potential to recapitulate early embryonic development through self-organisation and patterning in vitro . Objective – Establishing conditions mirroring in vivo early brain development and identifying underlying mechanisms using fish primary embryonic pluripotent stem (ES) cell. Methods – Generation of ES cell-derived aggregates in tissue culture. Live imaging (confocal, multiphoton), micropatterning, chemical and physical perturbations, computational image analyses of cell morphodynamics (movements, shapes) and tissue patterning.
 Gilmour D. et al. Nature. 2017
 Heisenberg CP. and Bellaiche Y. Cell. 2013
 Dahman C. et al. Nat Rev Genet. 2011
 Inman A. and Smutny M. Semin Cell Dev Biol. 2021
 Shahbazi MN. et al. Science. 2019
BBSRC Strategic Research Priority: Understanding the rules of life – Stem Cells.
Techniques that will be undertaken during the project:
- Zebrafish embryo as model system: generation of transgenic and knockout lines
- Microscopy (live & fixed specimen): confocal and multiphoton microscopy, selective plane illumination (light sheet) microscopy
- Genomic editing using Crispr/Cas9
- Cell culture assays (cell migration assays, gastruloids)
- Biochemistry (supported lipid bilayers))
- Computational image analysis and statistics (Fiji, Matlab, R)
- Biophysical tools: laser ablation, magnetic tweezer, cell confiner