Niche signalling and adult neurogenesis*

MRC Centre for Regenerative Medicine, 5 Little France Drive, Edinburgh, EH16 4UU

Background: Hippocampal neurogenesis underpins cognitive flexibility, and its dysfunction is implicated across many psychiatric illnesses. [1] Although much is known about the stem cells that give rise to adult hippocampal neurons, little is known about the biological role of the surrounding microenvironment, such as extracellular matrix (ECM). I hypothesised that ECM signalling can regulate hippocampal neurogenesis.

Methods: I developed two models of manipulating neurogenesis in the brains of adult mice. First, intracerebroventricular infusion of arabinoside cytaridine (Ara-C) effectively ‘re-boots’ neurogenesis by triggering a temporally predictable regenerative proliferation. In the second model, a single electroconvulsive seizure (ECS) robustly activates stem cells, increasing neurogenesis.

Results: Taking a candidate approach, I focused on Integrin beta 1 (Itgb1) as the major conduit between the cell and the ECM. I showed that Itgb1 is detectably expressed in vivo by cells in the proliferative phases of adult neurogenesis. I then studied its functional role by inducibly deleting the Itgb1 gene specifically from the stem cells. Unexpectedly, Itgb1 inducible knock-out (iKO) caused increased stem cell proliferation, in a cell-autonomous manner. Using a combination of Ara-C, ECS, and physiological follow-up experiments I established that Itgb1 negatively regulates stem cell activation, and subsequently neural, but not glial or oligodendroglial differentiation.

I then switched to a candidate-free approach, using laser-capture microdissection and RNA sequencing to identify transcriptional signatures at key time-points during hippocampal regeneration. Bioinformatic analysis identified an unexpected extracellular matrix protein as a possible novel regulator of stem cell activation. I validated this analysis and work to explore mechanisms is ongoing.

Conclusion: Integrin beta 1 regulates hippocampal stem cell activation, proliferation and neural differentiation. The first RNA-seq analysis of the regenerating niche identified novel candidate ECM regulators of hippocampal neurogenesis. Together these results suggest that extracellular matrix signalling can regulate adult hippocampal neurogenesis.

References

1. Kang E, Wen Z, Song H, Christian KM, Ming GL. Adult Neurogenesis and Psychiatric Disorders. Cold Spring Harb Perspect Biol, 2016, 8(9): pii: a019026. doi: 10.1101/cshperspect.a019026

Funded by: the MRC/MRF PsySTAR programme and the British/Israel Research Exchange (BIRAX) initiative

* entered into the PhD student poster competition