Dr R Lovell-Badge
Tuesday, November 12, 2019
Funded PhD Project (Students Worldwide)
This 4-year PhD studentship is offered in Dr Robin Lovell-Badge’’s Group based at the Francis Crick Institute (the Crick).
Adult Stem Cells (SCs) are tissue specific undifferentiated cells characterised by their self-renewal and differentiation properties. These unique features confer on SCs the ability to generate new cells lost during normal cell turn-over or trauma, but also in response to physiological challenges in some organs. SC populations are often heterogeneous and can fulfil additional roles, such as guidance of newly born neurons by radial glia, which also act as neural SCs. Resolving this heterogeneity and understanding the dynamics of these complex populations is important to be able to harness their regenerative potential.
We, and others, have characterised a population of adult SCs in the mouse pituitary , which is also present in the human gland. Initial analyses of SC progeny and proliferation rates suggested that this population was relatively quiescent. In agreement with this, it was shown that division of differentiated cells is sufficient to ensure the low pituitary cell-turnover . However, under physiological challenges, such as ablation of pituitary target organs like the adrenals and/or the gonads, SCs are mobilized; they proliferate and, in some cases, differentiate . While this highlights the regenerative properties of this population, it also suggests that these only operate in situations with substantial physiological changes.
To uncover mechanisms underlining this regulation, we performed single cell RNAseq. Unexpectedly, these show that in quiescent conditions some of the cells are primed for differentiation, and that this varies according to physiological states, revealing unanticipated receptivity and dynamism.
Pituitary SCs are mostly characterized by the expression of the transcription factors SOX2 and SOX9 , and represent a heterogeneous population. This is seen spatially, as they form an epithelium lining the endocrine parenchyma, but are also found within the parenchyma. Moreover, some SCs represent folliculo-stellate cells, a glial cell-like population known to support and harmonise endocrine function . The hierarchical relationship, and potentially differential properties of these populations are not known.
The aim of this project is to resolve aspects of this heterogeneity, and understand its functional relevance. Single cell RNAseq analyses in both quiescent and challenged conditions have successfully identified subpopulations within SCs. Novel genes differentially expressed within, and between single cell RNAseq datasets will be first validated by analysing transcript (RNAscope) or protein (immunostaining) localization, and in vitro, in SCs derived pituispheres. To explore hierarchical relationships between sub-populations, clonal lineage tracing using the R26R-Confetti reporter and Sox2/9CreERT2, or our newly developed more physiological, tamoxifen independent Sox2rtA allele will be used. Single cell clustering may be underlined by differences in proliferation; FUCCI sensors can be used to spatially resolve these differences. The functional relevance of distinct populations will be assessed by cell ablation using the inducible Diptheria toxin alleles (R26DTA or DTR). This requires sub-population specific drivers that may be already available or that we’ll generate using genome editing technologies. We expect that these analyses will help to understand how regenerative ability is blocked in normal conditions, and ultimately provide clues to unlock this potential in pituitary SCs, and other similarly quiescent SC populations, such as those in the CNS.
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 2020 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 (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) 13 NOVEMBER 2019. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.
Successful applicants will be awarded a non-taxable annual stipend of £22,000 plus payment of university tuition fees. Students of all nationalities are eligible to apply.
1. Haston, S., Manshaei, S. and Martinez-Barbera, J. P. (2018)
Stem/progenitor cells in pituitary organ homeostasis and tumourigenesis.
Journal of Endocrinology 236: R1-R13. PubMed abstract
2. Langlais, D., Couture, C., Kmita, M. and Drouin, J. (2013)
Adult pituitary cell maintenance: lineage-specific contribution of self-duplication.
Molecular Endocrinology 27: 1103-1112. PubMed abstract
3. Rizzoti, K., Akiyama, H. and Lovell-Badge, R. (2013)
Mobilized adult pituitary stem cells contribute to endocrine regeneration in response to physiological demand.
Cell Stem Cell 13: 419-432. PubMed abstract
4. Fauquier, T., Rizzoti, K., Dattani, M., Lovell-Badge, R. and Robinson, I. C. A. F. (2008)
SOX2-expressing progenitor cells generate all of the major cell types in the adult mouse pituitary gland.
Proceedings of the National Academy of Sciences of the United States of America 105: 2907-2912. PubMed abstract
5. Andoniadou, C. L., Matsushima, D., Mousavy Gharavy, S. N., Signore, M., Mackintosh, A. I., Schaeffer, M., . . . Martinez-Barbera, J. P. (2013)
Sox2+ stem/progenitor cells in the adult mouse pituitary support organ homeostasis and have tumor-inducing potential.
Cell Stem Cell 13: 433-445. PubMed abstract