Understanding increased gene dosage effects in Down Syndrome embryonic mouse hearts
Key information
Research topics
This is a summer student position supervised by Zuzanna Jablonska in Victor Tybulewicz's lab.
Introduction to the Science
Down syndrome, caused by trisomy of human chromosome 21 (Hsa21), is a gene dosage disorder that results in several pathologies including learning and memory deficits, craniofacial alterations, and congenital heart defects. To study these pathologies, we use the Dp1Tyb mouse model, which contains a duplication of 23Mb of mouse chromosome 16 (Mmu16) which is orthologous to part of Hsa21. This region contains 144 protein coding genes, which are therefore present in three copies instead of the usual two. Dp1Tyb mice develop congenital heart defects similar to the ones seen in people with Down syndrome. These include ventricular and atrio-ventricular septal defects, which are observed in the developing hearts of Dp1Tyb mice.
About the Project
Heart septation depends on key contributions from two major cell types: the second heart field and the cardiac neural crest, which help remodel the early heart tube into a four-chambered heart. For this process to happen correctly, different signalling pathways need to carefully coordinate how these cell types contribute to forming the septum. This project will focus on understanding the role of the neural crest cells during heart septation and how increased dosage of genes in the Dp1Tyb mice affects this process. To study this, we will use a fluorescent reporter system that is activated by Cre recombinase. This will allow us to identify and track neural crest-derived cells in developing mouse hearts.
By joining this project, you will gain hands-on experience with a range of developmental biology techniques, including:
- Embryo dissection - collecting embryonic hearts at key developmental stages.
- Immunofluorescence and confocal imaging - labelling specific cell types and capturing high-resolution images.
- Image analysis - using software tools to quantify how neural crest-derived cells contribute to septation.
Candidate background
The post holder should embody and demonstrate the Crick ethos and ways of working: bold, open and collegial. The candidate must be registered at a UK Higher Education Institution, studying in the UK and must have completed a minimum of two years’ undergraduate study in a relevant discipline, and on track to receive a final degree grade of 2:1 or 1. In addition, they should be able demonstrate the following experience and key competencies:
- This project is ideal for students curious about developmental biology, genetics, microscopy, or congenital heart defects. You will get to work closely with a research team, learn techniques widely used in biomedical research, and contribute to understanding how the heart forms.
- Good knowledge in relevant scientific area(s)
- Good written and spoken communication skills
- Ability to work independently and also capable of interacting within a group
References
1. Lana-Elola, E., Aoidi, R., Llorian, M., Gibbins, D., Buechsenschuetz, C., Bussi, C., . . . Tybulewicz, V.L.J. (2024)
Increased dosage of DYRK1A leads to congenital heart defects in a mouse model of Down syndrome.
Science Translational Medicine 16: eadd6883. PubMed abstract
2. Lana-Elola, E., Watson-Scales, S., Slender, A., Gibbins, D., Martineau, A., Douglas, C., . . . Tybulewicz, V.L. (2016)
Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel.
eLife 5: e11614. PubMed abstract