Analysis of the cellular basis of heart septation and how this is perturbed in down syndrome

This 4-year PhD studentship is offered in Dr Victor Tybulewicz’s Group based at the Francis Crick Institute (the Crick) & Dr Jeremy Green’s Group based at King’s College London.

The mammalian heart is divided during embryonic development into four chambers. Failure of this division (septation) is one of the most common congenital birth defects and has important morbidity and mortality consequences. Heart septation defects are a prevalent phenotype in Down Syndrome (DS), both in humans and in a mouse DS model (Dp1Tyb) recently created in the Tybulewicz lab. The Dp1Tyb model mimics the extra copy of human chromosome 21 (Hsa21) seen in DS individuals by duplicating a region of mouse chromosome 16 (Mmu16) that is orthologous to most of Hsa21. It also replicates the main phenotypes, including cognitive deficits as well as the characteristic craniofacial alterations and heart septation abnormalities. The Tybulewicz lab is using mouse genetics to identify the genes on Hsa21 that are required in three copies to cause these septation defects. Current work has shown that duplication of a region of just 25 genes on Mmu16 is sufficient to cause heart defects and that this region must contain at least 2 causative genes. The Green lab focuses on processes of morphogenesis and has developed imaging and analytical computational methods for establishing which specific cell behaviours collectively generate particular structures during embryonic growth. These include image acquisition approaches, image processing and statistical analysis.

This project will apply these methods to study septation in both the normal (wild type) and the DS mouse heart. Specifically, the project will quantify growth and shaping of the septa and the “endocardial cushions” which are structures that fuse and form the atrioventricular valves, thereby separating atria from ventricles. A key tool in these studies will be the ability to sparsely label cells in the developing heart and then follow the behaviour of clones of cells over time, quantitating proliferation, movement, oriented cell division and cell shape change. Such approaches will require use of the appropriate mouse genetic strains (e.g. Confetti or mTmG strains, combined with an inducible Cre recombinase). Furthermore, the project will also develop methods for growing embryonic hearts in explant cultures, which will open up the exciting possibility of using live imaging methods to study septal growth and endocardial cushion fusion. Such a culture system would open up a large area of investigative tools to study the process of heart septation and to understand the developmental origins of heart defects more generally.

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 2019 and will register for their PhD at King’s College London.

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 (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) NOVEMBER 13 2018. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.