How biological timing is encoded in the genome is a fundamental question in biology. In development, the pace of developmental programs is a source of evolutionary change. Larger species develop at a slower pace compared to smaller species despite using conserved genetic programs, and the pace determines the rate of development of the whole organism, its size, and ultimately the length of time that embryogenesis takes 1,2. Moreover, imbalances in the speed of tissue development and stem cell differentiation can result in tissue overgrowth or deficits. Therefore, controlling the speed of differentiation is essential for the size, function and shape of developing organs.
To investigate the molecular mechanisms that control developmental timing, we and others have developed comparative stem cell models between species 3,4. Recently, we showed that the embryonic differences in developmental tempo can be recapitulated in stem cell differentiation models to motor neurons. The slower progression of human differentiation compared to mouse allowed the search for the mechanisms that determine developmental tempo. We found that mouse proteins are degraded twice as fast as human proteins, mirroring the differences in developmental tempo. In silico, decreasing the degradation rate of key transcription factors explained the slower temporal progression in human compared to mouse 3. Now, this work opens up several questions: (1) does protein turnover control developmental tempo in vivo?, (2) Is protein turnover a general mechanism of temporal control?, and (3) what controls protein turnover?
One developmental process to study and compare developmental timing across species in vivo and in vitro is blastocyst development, as we can culture pre-implantation embryos and make use of embryonic stem cell models. Whereas the blastocyst is formed at day 3 post fertilization in mouse, it takes five days during human embryo development 5. Further, mouse blastocyst development can be physiologically slowed down for extended periods of time during diapause in response to adverse nutrient conditions and its timing can be reset upon diapause exit 6.
In this project the candidate will establish ex vivo diapause in mouse cultured embryos and induce pausing of mouse embryonic stem cells in vitro to investigate the mechanisms of tempo modulation within a species. The candidate will make use of single cell quantitative approaches and live imaging to determine dynamics of protein turnover, use genome-wide transcriptomic approaches to identify regulators of diapause entry and exit, and employ pharmacological and genetic perturbations to examine the molecular control of developmental timing. Overall, the project offers the exciting possibility to study tempo modulation in the whole organism within a single species and will help uncover the molecular mechanisms that control developmental timing.
Applicants should be curious about developmental biology and embryonic stem cells. A background on cell or molecular biology, as well as skills in bioinformatics or computational approaches would be useful, but ample opportunities for training will be provided.
How to apply
All applications for PhD Studentships at the Babraham Institute need to be made using the University of Cambridge Graduate Application Portal regardless of funding source.
Please see the “Applying for a PhD” pages on our website for further details of the application process.
(For certain projects it is essential that you contact the Group Leader proposing the project BEFORE submitting your application via the University of Cambridge Graduate Application Portal to discuss possible funding options. Please see individual project descriptions for details.)
We hope to be able to invite short-listed applicants to attend our Institute Graduate Open Day on Wednesday, 19th January 2022 for a series of interviews. This will give applicants an opportunity to meet Group Leaders and their research groups, as well as receiving a tour of our research facilities. Reasonable travel expenses will be paid to those invited.
Students will not be able to take up an award unless they meet all University eligibility criteria and are successful in securing admission to the University. In addition, they will not be able to apply for a visa (if needed) until they hold an unconditional offer from the University.
The deadline for submission of applications via the Graduate Application Portal is Thursday, 2nd December 2021. Incomplete applications will not be considered.
If you would like more information, or have any questions not answered on our website or the University of Cambridge Graduate Application Portal, please contact us on [Email Address Removed].