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Elucidating the mechanisms of mechanochemical crosstalk between ion transport, mitotic spindle and chromosome dynamics during breast epithelial morphogenesis


   Biological Sciences

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  Dr S Elias, Dr R Murrell-Lagnado  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Polarised epithelial cell divisions represent a fundamental mechanism for tissue maintenance and morphogenesis, their dysregulation often leads to developmental disorders and cancer (1). A dividing cell must overcome many challenges to produce two daughter cells that have a correct shape and position and that inherit equal amounts of the genetic material. Mitotic progression and outcome are defined by spectacular changes in cell morphology and mechanics, and rearrangements in the microtubule (MT) and actin cytoskeleton. Recent evidence has suggested that ion and water fluxes across the plasma membrane (PM) play a key role in the regulation of the mechanics of mitosis (2). Yet the mechanisms linking the PM to cell shape and size and the mitotic machinery in mammalian epithelial cells remain poorly understood. Using a proteomic screen, we recently identified the PM-associated protein S100A11A (S100 Ca2+-binding protein A11), as being involved in the control of PM dynamics during mitosis in breast epithelial cells. Our preliminary observations show that S100A11 knockdown results in spindle mis-assembly, chromosome mis-segregation, cytokinesis defects and asymmetric partitioning of PM resulting in two daughter cells that differ in size and shape. S100A11A is a regulator of intracellular Ca2+ concentration and cytoskeleton dynamics (3) and is known to interact with TRPM7 (transient receptor potential melastatin 7), a calcium permeable ion channel that also possesses a kinase domain (4). Our hypothesis is that regulation of TRPM7 by S100A11 is critical for its role in mitosis. The aim of this project is, to 1) understand how S100A11A regulates the function and PM localization of TRPM7; 2) assess the impact of S100A11 on Ca2+ signalling and how this links to cell size and shape during mitosis; and 3) determine how this influences mitosis outcome and epithelial morphogenesis.

This collaborative project will provide the PhD student with a cutting-edge multidisciplinary training in cell biology and biotechnology combined with advanced immunofluorescence imaging. By combining CRISPR/Cas9-based acute degradation of S100A11 and super-resolution and 3D quantitative live and Ca2+ imaging, the PhD candidate will investigate the impact of S100A11-loss-mediated defects in cell shape and size on the spindle-kinetochore dynamic interaction and determine how this affects chromosome alignment and segregation, mitotic spindle assembly and orientation as well as cytokinesis and the fate and position of the daughter cells. The PhD student will further extend the study in breast 3D organoids combined with 3D live and confocal imaging to assess the impact of S100A11-loss-mediated defects in cell division on epithelial integrity and differentiation.

This project will provide a significant mechanistic insight on the mechanisms bridging PM dynamics, ion transport, cell shape, spindle assembly and chromosome stability maintenance for correct mitotic progression and outcome to ensure proper epithelial architecture and prevent malignant transformation.

If you are interested in this project, please follow this link https://southcoastbiosciencesdtp.ac.uk/project/elucidating-the-mechanisms-of-mechanochemical-crosstalk-between-ion-transport-mitotic-spindle-and-chromosome-dynamics-during-breast-epithelial-morphogenesis/ or contact the lead supervisor – Dr Salah Elias at [Email Address Removed]) for more information.

Requirements for Applicants

Candidates should have a BSc/MSci 2:1 and/or Masters (MSc or MRes) at Merit/Distinction level (>60%) and/or evidence of significant relevant professional experience equivalent to Masters level. SoCoBio welcomes applications from candidates with sustained experience beyond their undergraduate degree level that is specifically relevant to biosciences research. This includes students with degrees in science or engineering-disciplines outside of biology

All students whose first language is not English must be able to provide recent evidence that their spoken and written language skills are adequate for the doctoral study – normally an IELTS qualification with a minimum score of 6.5 in all sections or proof of a previous degree taught in English or substantial work experience in the UK.

How to apply

Please complete the University of Southampton online application by following this link Apply Now

 A step-by-step guide to apply can be found by following this link https://southcoastbiosciencesdtp.ac.uk/apply/   

Application deadline: Midnight, Monday 9 January 2023



Funding Notes

This four-year programme comprises two laboratory ‘rotations’ in the first year, followed a project jointly supervised by researchers from two of the host institutions in years 2-4. Funding will cover tuition fees at the UK rate only, a Research Training and Support Grant (RTSG) and stipend. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

1. Santoro, A. et al EMBO Rep (2016) 17, 1700-1720
2. Rizzelli et al. Open Biol (2020) 10(3):190314
3. Zhang et al. Front. Cell Dev. Biol (2021) doi: 10.3389/fcell.2021.693262
4. Cordier et al. (2021) Cancers https://doi.org/10.3390/cancers13246322

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