Weekly PhD Newsletter | SIGN UP NOW Weekly PhD Newsletter | SIGN UP NOW

Understanding mechanisms driving tissue morphogenesis and cell fate during early embryonic development


   School of Life Sciences

This project is no longer listed on FindAPhD.com and may not be available.

Click here to search FindAPhD.com for PhD studentship opportunities
  Dr M Smutny  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

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 [1]. 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 [2]. 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 [1]. 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?).

Project outlines

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 [3]. 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 [4]. 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 [5]. 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.

References:

[1] Gilmour D. et al. Nature. 2017

[2] Heisenberg CP. and Bellaiche Y. Cell. 2013

[3] Dahman C. et al. Nat Rev Genet. 2011

[4] Inman A. and Smutny M. Semin Cell Dev Biol. 2021

[5] 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)

- Optogenetics

- Biochemistry (supported lipid bilayers))

- Computational image analysis and statistics (Fiji, Matlab, R)

- Biophysical tools: laser ablation, magnetic tweezer, cell confiner


Funding Notes

Studentships provide:
Full Tuition fees
A tax free annual stipend for living expenses (in academic year 2022-23 this was £17,668)
A travel / conference budget
A generous consumables budget
Use of a laptop for the duration of the programme.
PhD saved successfully
View saved PhDs