Migrating neurons in the cerebral cortex

This project is now closed

Signalling and transcriptional control of quiescence and activity of neural stem cells

Project supervisor: François Guillemot (Molecular Neurobiology)

New neurons are added to the adult hippocampus, where they have important roles in memory formation. The neural stem cells (NSCs) that generate these new neurons become quiescent (stop dividing) in ageing animals, which might contribute to memory loss in old age. The BMP and Notch signalling pathways and the transcription factors FoxO have been shown to inhibit NSC divisions and might contribute to neurogenesis decline in old animals. Stem cell quiescence in tissues such as blood and muscles involves profound changes in cell physiology in addition to cell cycle arrest. Whether similar changes occur in quiescent NSCs is not known.

We have used cultures of NSCs to study the molecular control of stem cell divisions, as NSCs in the brain are present in low numbers. Using this model, we have shown that the transcription factor Ascl1 promotes NSC divisions (Castro et al., 2011) and more recently that BMP inhibits NSC divisions in culture as it does in vivo (unpublished).

The aims of the project are:

  1. Examine the effect of BMP on gene expression and metabolism in cultured NSCs to address whether cell cycle arrest of NSCs is associated with changes in cell physiology (e.g. energy metabolism, protein translation) as in other tissues, and determine whether Notch and FoxO induce similar or distinct changes in NSCs.
  2. Examine the molecular mechanisms underlying NSC quiescence by studying the impact of BMP, Notch and FoxO on the activity of Ascl1 and other transcription factors known to control stem cell activity.
  3. Validate results obtained in NSC cultures by examining markers of NSC quiescence identified above in mice with inactivated BMP, Notch or FoxO, old mice and mouse models of Alzheimer’s disease.

This project will contribute to a better understanding of how neural stem cells are affected by ageing and neurodegenerative diseases.

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BMP-treated neural stem cell culture stained for the stem cell markers GFAP (green) and nestin (red) and for the general nuclear marker Dapi (blue).

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