The nuclear connection to 3D cell polarity and migration (Liverpool)
Cell migration in three dimensional matrices is fundamental for many developmental processes and its deregulation can lead to a vast variety of pathologies including cancer cell invasion and impaired cell locomotion in ageing cells. One of the central tasks of any cell migrating in dense three dimensional (3D) matrices in a polarized manner is the directional movement of the nucleus. Cell migration in 3D depends on the cells ability to deform the nucleus to squeeze through tight matrix pores. We have developed a FRET nuclear force transmission biosensor, based on mNesprin2, an outer nuclear membrane (ONM) protein that connects the cytoskeleton to the nuclear interior, which allows us to accurately measure forces applied on the ONM. Our unpublished findings show that the nucleus is being pulled forward from the cell front in an actin dependent manner. The central question of this project will be to elucidate which cytoskeletal and nuclear envelope proteins are required to effectively perform force transmission and just how much force is needed to move the nucleus though matrix and to the nucleus. You will use a range of cell biological techniques and a combination Laser scanning microscopy, super-resolution microscopy and Atomic Force Spectroscope, to quantitatively determine the force needed to displace the nucleus and apply this knowledge to investigate the impact of mutations of nuclear envelope proteins in genetic diseases involved in premature ageing, like progeria.
For further information see the website: https://www.liverpool.ac.uk/translational-medicine/
Please submit a full CV and covering letter directly to [email protected]
This is a 4 year BBSRC studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£14,057 for 2015-16). The PhD will start in September 2016. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. There are 2 stages to the application process.
Yu X*, Zech T*, McDonald L, Gonzalez EG, Li A, Macpherson I, Schwarz JP, Spence H, Futó K, Timpson P, Nixon C, Ma Y, Anton IM, Visegrády B, Insall RH, Oien K, Blyth K, Norman JC, Machesky LM. (2012) N-WASP coordinates the delivery and F-actin-mediated capture of MT1-MMP at invasive pseudopods. J Cell Biol. Oct 29;199(3):527-44. *equal contribution