Close
Supervisors names
Gabriel Galea
Rob Hynds
Background:
The Galea lab studies severe malformations of the brain and spinal cord called neural tube defects. We use a combination of animal, computational and iPSC models aiming to improve prevention and patient outcomes for these conditions. Ongoing projects include modelling rare forms of spina bifida, mechanistically studying how molecular-level processes set tissue-level rates of development, and using iPSCs from patients who have spina bifida to understand genetic causes of this debilitating condition. The group has internationally-recognised expertise in advanced microscopy (e.g. Galea et al Nat Commun 2021), embryo live imaging (e.g. Maniou et al PNAS 2021) and dissecting the biomechanical basis of central nervous system (CNS) development (e.g. Ampartzidis et al Dev Biol 2023).
The cells of the embryonic CNS are called neuroepithelial cells. In the head-end of the embryo they differentiate from thickening of the epiblast. In the spinal cord they differentiate from a progenitor population called neuromesodermal progenitors (NMPs). NMPs reside in a niche under the neuroepithelium, into which they must integrate. This is the cell equivalent of jumping onto a moving train. The neuroepithelium is a highly dynamic tissue which rapidly changes its shape and moves as the embryonic neural tube closes.
The mechanisms by which committed progenitors integrate into this pre-existing epithelium are unknown. Understanding this process will have implications for preventing birth defects and regenerative medicine. For example, next-generation organoid technologies will require multiple interacting cell types to be integrated into mini-organs. This PhD will help us learn from nature to guide future regenerative medicine techniques.
Aims:
Depending on the student’s interest, we will:
- Apply advanced imaging techniques such as correlative light and electron microscopy (CLEM) to relate changes in progenitor cell shape with molecular identity as they integrate into the neuroepithelium, with functional testing using antagonists in whole embryo culture and analysis of mouse genetic models of neural tube defects.
- Use our established model of iPSC differentiation from an epiblast-like to neuroepithelial state to study molecular regulation of cell shape change, including cells from patients with mutations in relevant genes.
- Collaborate with colleagues in UCL and internationally to apply computational models investigating requirement for properties such as changing cell-cell versus cell-ECM adhesion in progenitor integration, explaining the mechanical impact of genetic mutations.
Methods:
Specialised techniques tailored to the aims selected by the student will be complemented with confocal/two-photon microscopy, molecular biology techniques such as PCR, computational image analysis, and embryo microdissection. The student would also be involved in the lab’s public engagement activities and would have opportunities to be involved in teaching.
Timeline:
The student would learn core research techniques and refine their research direction over the first six months, completing establishment of their model with descriptive and validation endpoints within the fist year. The second year will prioritise functional application, for example by antagonising potential mediators of progenitor integration in mouse whole embryo or iPSC culture. In the third year they will apply findings made to disease states, such as in genetic models of spina bifida.
Contact
Gabe Galea, g.galea@ucl.ac.uk