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Regulation of adult brain stem cells by Sonic Hedgehog

  • Full or part time
    Dr F Guillemot
  • Application Deadline
    Tuesday, November 12, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

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

The brain is a highly plastic organ that uses a variety of mechanisms to adapt its activity to the environment and allow the organism to navigate a changing world. A major mechanism of brain plasticity is the generation and wiring of new neurons in the adult hippocampus, through the lifelong activity of hippocampal stem cells. Adult-born hippocampal neurons have important roles in learning and memory and in mood regulation [1, 2].

The mechanisms that control the proliferation of stem cells in the hippocampus and ensures the maintenance of neurogenesis throughout life remain poorly understood. We have previously identified an essential role of the transcription factor Ascl1 and its degradation by the ubiquitin ligase Huwe1 in controlling the proliferation of hippocampal stem cells [3, 4]. More recently, we have discovered that the signalling molecule Sonic Hedgehog (Shh), produced by a component of the hippocampal stem cell niche that had so far escaped attention, oligodendrocytes, controls the level of proliferation of hippocampal stem cells. Shh acts by blocking the degradation of Ascl1 by Huwe1 and thereby upregulates Ascl1 expression in hippocampal stem cells [4]. This discovery raises a number of interesting questions which will be addressed during the PhD thesis, regarding the mechanisms driving lifelong changes in hippocampal stem cell properties, the role of physiological stimuli in the regulation of adult neural stem cell activity, and whether pharmacological manipulations of Shh signalling can restore healthy levels of hippocampal neurogenesis in animal models of neurodegenerative disease.

The specific questions that will be investigated in the PhD project include:
1. How is Shh expression by a small subset of oligodendrocytes in the hippocampal niche controlled, e.g. by neuronal activity or by a distinct oligodendrocyte lineage.
2. How is the production of Shh by oligodendrocytes modulated by physiological states (e.g. physical exercise, enriched environment) and in animal models of pathologies (e.g. Alzheimer disease) known to regulate hippocampal neurogenesis.
3. Whether divergence in the expression pattern of Shh in oligodendrocytes might explain the different temporal profiles of hippocampal neurogenesis observed in different mammalian species, e.g. mice versus guinea pigs or marmosets (a primate species).

This project will provide insights into the lifelong regulation of hippocampal neurogenesis and might suggest strategies to stimulate hippocampal function and prevent cognitive decline in old age and neurological disease.

The student will be trained into the diverse experimental approaches needed to carry out the project, including:
- Genetic and pharmacological approaches in mice to manipulate Shh signalling in oligodendrocytes and hippocampal stem cells.
- Analysis of Shh localisation in the hippocampal niche and of the interaction between oligodendrocytes and hippocampal stem cells using high resolution microscopy techniques.
– Single cell RNA sequencing to analyse oligodendrocyte diversity and the mechanisms controlling Shh expression by a subset of oligodendrocytes.

Candidate background
This project would be particularly appropriate for candidates with previous training in neuroscience and/or stem cell biology.

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.

Funding Notes

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.

References

1. Snyder, J. S. (2019)

Recalibrating the relevance of adult neurogenesis.

Trends in Neurosciences 42: 164-178. PubMed abstract

2. Urbán, N. and Guillemot, F. (2014)

Neurogenesis in the embryonic and adult brain: same regulators, different roles.

Frontiers in Cellular Neuroscience 8: 396. PubMed abstract

3. Andersen, J., Urbán, N., Achimastou, A., Ito, A., Simic, M., Ullom, K., . . . Guillemot, F. (2014)

A transcriptional mechanism integrating inputs from extracellular signals to activate hippocampal stem cells.

Neuron 83: 1085-1097. PubMed abstract

4. Urbán, N., van den Berg, D. L. C., Forget, A., Andersen, J., Demmers, J. A. A., Hunt, C., . . . Guillemot, F. (2016)

Return to quiescence of mouse neural stem cells by degradation of a proactivation protein.

Science 353: 292-295. PubMed abstract

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