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Rick Livesey

Mammalian neural stem cell biology, fundamental and applied

The cerebral cortex, which makes up three quarters of the human brain, is the part of the nervous system that integrates sensations, executes decisions and is responsible for cognition and perception. Given its functional importance, it is not surprising that diseases of the cerebral cortex are major causes of morbidity and mortality. Understanding the biology of cortical neural stem cells is essential for understanding human evolution, the pathogenesis of human neurodevelopmental disorders and the rational design of neural repair strategies in adults. During embryonic development, all of the neurons in the cortex are generated from a complex population of multipotent stem and progenitor cells. Much of the research in the lab centres on the cell and molecular biology of cortical stem cells. We are particularly interested in the molecular mechanisms controlling multipotency, self-renewal and neurogenesis, and how these are coordinated to generate complex lineages in a fixed temporal order. A number of ongoing projects in the group address the functional importance of transcriptional and epigenetic mechanisms in this system.

In the other major strand of research in the group, we have developed methods for directing differentiation of human pluripotent stem cells to cortical neurons, via a cortical stem cell stage. Human stem cell-derived cortical neurons form functional networks of excitatory synapses in culture. We are using this system for studies of human neural stem cell biology and to generate models of cortical diseases. Our initial focus has been on dementia, where we have used stem cells from people with Down syndrome and from patients with familial Alzheimer’s disease to create cell culture models of Alzheimer’s disease pathogenesis in cortical neurons. We are using those models to study Alzheimer’s disease pathogenesis and the efficacy of current therapeutic strategies.

Lab members: Jessica Alsio, Therese Andersson, Chiba Ene, Peter Kirwan, Joao Pereira, Nathalie Saurat, Yichen Shi, James Smith, Anthony Walsh

Visit group website at the Gurdon Institute

Key publications:

1. Pereira, J.D., Sansom, S.N., Smith, J., Dobenecker, M.W., Tarakhovsky, A., and Livesey, F.J. (2010). Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex. Proc Natl Acad Sci U S A 107, 15957-15962.

2. Andersson, T., Rahman, S., Sansom, S.N., Alsio, J.M., Kaneda, M., Smith, J., O'Carroll, D., Tarakhovsky, A., and Livesey, F.J. (2010). Reversible block of mouse neural stem cell differentiation in the absence of dicer and microRNAs. PLoS ONE 5, e13453.

3. Subkhankulova, T., Yano, K., Robinson, H.P., and Livesey, F.J. (2010). Grouping and classifying electrophysiologically-defined classes of neocortical neurons by single cell, whole-genome expression profiling. Front Mol Neurosci 3, 10.

4. Sansom, S.N., Griffiths, D.S., Faedo, A., Kleinjan, D.J., Ruan, Y., Smith, J., van Heyningen, V., Rubenstein, J.L., and Livesey, F.J. (2009). The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis. PLoS Genetics, 5, e1000511.

5. Sansom, S.N and Livesey, F.J. Gradients in the brain: the control of the development of form and function in the cerebral cortex. (2009). Cold Spring Harb Perspect Biol 1:a002519.