(BBSRC DTP) Maintenance of tissue integrity during organ growth, development and repair

Cell division is fundamental to the growth and repair of all tissues, but is inherently a disruptive process that splits and separates daughter cells. As such, rapid reestablishment of daughter cell-cell junctions is critical to maintain tissue integrity in proliferating tissues. For example, during vascular development, daughter cells can detach and disperse from growing tissues if adherens junctions are perturbed. Yet, how daughter cells rapidly rebuild cell-cell junctions following division and prevent this disruption is unclear.

The Herbert lab employs a highly multidisciplinary approach to investigate tissue formation, encompassing in-vivo genetic and live-imaging studies in the zebrafish model system, in-vitro ‘omics’ and micropatterning approaches in primary human cells, in-silico modelling methods and CRIPSR gene-editing. Using such techniques, we previously revealed that cell division is essential to the growth of new blood vessels (Costa, 2016, Nature Cell Biology). Moreover, recent unpublished work using high spatiotemporal resolution in vivo live-imaging studies of vascular development reveals that, following division, reassembly of cell-cell junctions involves local actin remodelling at the interface of daughter cells. We find that precise recruitment of the actin-regulator, cortactin, specifically to sites of nascent cell-cell junction formation is linked to the rapid ‘zippering’ of new junctions that quickly re-seals any gaps in the tissue. As such, post-mitotic activation and relocation of cortactin, followed by local actin remodelling, is likely essential to maintenance of tissue integrity during organ formation.

To define the interrelationship between post-mitotic actin remodelling and maintenance of tissue integrity, this project will:

(1) Define the role of actin remodelling in post-mitotic junction zippering: Using in-vivo live-imaging of actomyosin dynamics and computational models of mitosis, we will explore the function of actin remodelling in post-mitotic cell-cell junction zippering. Moreover, using novel chromophore-assisted light inactivation (CALI) tools to perturb actomyosin, we will define the precise function of post-mitotic cortactin-mediated actin remodelling in this process.

(2) Identify signals and mechanical cues that initiate post-mitotic junction zippering: Using pharmacological, genetic and micropatterning approaches, we will define whether cadherin and/or midbody-derived mechanical cues can trigger post-mitotic reassembly of cell-cell junctions.

(3) Define the role of junction zippering in the maintenance of tissue integrity: Using approaches established above to perturb post-mitotic junction reassembly, we will determine the importance of this phenomenon in maintaining tissue structure, behaviour and function. In particular, we will expand studies to non-vascular tissues and explore broad conservation of this process in maintaining tissue integrity, growth and repair.

www.herbertlab.com

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website www.manchester.ac.uk/bbsrcdtpstudentships