Coordination of tissue architecture with growth control

This 4-year PhD studentship is offered in Dr Nic Tapon’s Group based at the Francis Crick Institute (the Crick).

Tissue architecture is intimately coupled with growth control, particularly in epithelial tissues, where organised cell-cell contacts are essential to prevent excess proliferation and invasive behaviour. Indeed, disrupted tissue architecture and cell polarity are features of many human tumours. The Hippo tumour suppressor pathway, which was discovered in the fruit fly Drosophila, has been proposed to act as a key growth-regulatory sensor of tissue architecture and is implicated in mammalian tumorigenesis. At its heart is the pro-growth transcriptional co-activator Yorkie (Yki – YAP/TAZ in mammals). Nuclear Yki binds to transcription factors such as Scalloped (TEAD in mammals) and promotes the expression of genes involved in growth, proliferation and stem cell identity. Yki/YAP activity is normally tightly restricted by the Hippo core kinase cascade, composed of an upstream kinase (Hippo) and a downstream kinase (Warts). Numerous experiments suggest that Yki/YAP activity is modulated by tissue architecture via cell polarity proteins and the actin cytoskeleton. To understand how Hippo signalling can be exploited for cancer therapy and regenerative medicine, it is essential to unravel its regulatory inputs and links with tissue architecture.
The RASSF family of proteins (RASSF1-RASSF10) has been implicated in both growth control and tissue architecture. Several family members are candidate tumour suppressors linked with Hippo signalling. Our work has identified Drosophila RASSF8 as a modulator of cell junction dynamics and a putative Hippo pathway downstream effector. In mammals, RASSF8 is part of the ASPP/PP1 complex, which has been reported to promote YAP activity by reversing its inhibitory phosphorylation by the Hippo core kinase cascade. We have also shown that Drosophila RASSF (the RASSF1-6 ortholog) antagonises Hippo signalling via the STRIPAK PP2A phosphatase complex, which directly dephosphorylates Hippo kinase.
We are currently exploring the function of Drosophila RASSF8, 9 and 10 as components of PP1 phosphatase complexes that controls tissue architecture via the apico-basal and planar cell polarity pathways. Furthermore, we have generated mouse knockout models of the Drosophila RASSF8 orthologs, RASSF7 and RASSF8, as well as the putative mammalian STRIPAK regulator RASSF3.
The proposed project will use state-of-the-art Drosophila and mouse genetic approaches to understand the function of RASSF proteins in tissue architecture and growth control. We will use intravital imaging of developing Drosophila tissues to visualise the effects of disruption of RASSF family members on tissue organisation and cell polarity in both epithelial cells and in neuronal stem cells. We will use our mouse knockout models to thest the relevance of our Drosophila findings in mammalian development and tumorigenesis. Furthermore, we will perform proteomic and biochemical analyses in order to identify substrates for the RASSF-associated phosphatase complexes. To understand the effects of dephophorylation of these substrates on tissue architecture, we will introduce relevant mutations into flies using CRISPR/Cas9 genomic engineering. This will allow us to gain an in-depth understanding of the coupling between tissue architecture, cell polarity and growth control during development and tumorigenesis.
This is just an example of the projects available in this research group. The precise project will decided on in consultation with the supervisor.

Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2017 and will register for their PhD at one of the Crick partner universities (Imperial College London, King’s College London or UCL).

Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.

APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE BY 12NOON GMT NOVEMBER 14TH 2016. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.
https://www.crick.ac.uk/about-us/jobs-and-study/phd-programme/