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Dynamic cell fate decisions: linking mechanical signals and protein expression dynamics in the developing eye to understand human developmental disorders


Project Description

Inherited developmental disorders account for much of childhood visual impairment. Development of the eye requires cell fate decisions that balance stem cell proliferation and differentiation. These are controlled by intrinsic factors, such as gene network dynamics and extrinsic factors such as mechanical signals from the surrounding tissue and extracellular matrix. Mechanical signals are crucial during eye development as mutations in the mechano-transducer YAP lead to coloboma in humans, a rare developmental disorder arising from failure in optic cup folding and fusion. Furthermore, coloboma is often accompanied by microphthalmia a disorder arising from misregulation of proliferation and cell fate. The co-occurrence of coloboma, a structural disorder of the eye, and microphthalmia, a cell fate disorder, suggests a mechanistic link between the mechanical environment and cell fate in the developing eye.

In recent years, our understanding of how stem cells make fate transitions has been transformed by the application of single cell technologies. New single cell live imaging approaches are revealing the importance of protein expression dynamics, particularly pulsatile and short-period oscillatory expression of the Hes genes, on the control of cell fate. However how mechanical signals are integrated with expression dynamics of cell fate during embryonic development is unknown. Our recent data shows that the neural stem cells undergo changes in the expression dynamics of the Notch target gene Hes5 as they make fate decisions. Further, Hes5 has periodic and oscillatory expression in retinal progenitor cells. This is an inter-disciplinary PhD project that will integrate quantitative and dynamic live imaging of Hes gene transcriptional activity in primary retinal stem cells and retinal organoids/”mini-organs”.
We aim to

1. Characterise
a) morphological and mechanical changes in single retinal progenitor cells during early eye development
b) expression dynamics of the Hes genes in retinal stem cells during optic cup formation

2. Determine the impact of mechanical signals, different extracellular matrix proteins and YAP signalling on retinal stem cell expression dynamics and fate decisions

The outcome of this project will be to further the understanding of the aetiology of ocular developmental disorders. Specifically, how and which extracellular matrix proteins promote proliferation over differentiation, a key step in developing potential postnatal treatments for developmental ocular disorders.

The student will learn molecular biology techniques, all aspects of cell culture including generation of eye organoids/”mini-organs”, live imaging with various imaging modalities including laser-scanning confocal microscopy, image analysis and design and application of CRISPR-Cas9 genome engineering to generate gene expression reporters. The student will also interact with mathematicians within the University of Manchester and collaborators in the University of St Andrews to help explore mathematical models of eye development and investigate the multiple complex feedbacks that occur between mechanical signals and cell-fate.

Entry Requirements:
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with previous laboratory experience, particularly in cell culture and confocal microscopy, are encouraged to apply.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Quantitative single-cell live imaging links HES5 dynamics with cell-state and fate in murine neurogenesis. Manning CS, Biga V, Boyd J, Kursawe, J, Ymisson B, Spiller DG, Sanderson CM, Galla T, Rattray M, Papalopulu N. Nature Communications 2019 Jun 27;10(1):2835.

Hippo-Yap signalling in ocular development and disease. Lee M, Goraya N, Kim S, Cho SH. Developmental Dynamics 2018. 247:794-806

Excitable Dynamics and YAP-Dependent Mechanical Cues Drive the Segmentation Clock. Hubaud A, Regev I, Mahadevan L, Pourquie. Cell 2017 171, 3 668-682.e11

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