Rick Livesey MB BChir PhD, Wellcome Trust Group Leader, Member of the Biochemistry Department.
Development, evolution and degeneration of the brain
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.
• Pereira JD, Sansom SN, Smith J, Dobenecker MW, Tarakhovsky A and Livesey FJ (2010) Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex. Proc National Academy of Science USA, 107, 15957-15962.
• Livesey FJ (2012) Stem cell models of Alzheimerâ€™s disease and related neurological disorders. Alzheimers Res Ther Alzheimers Research Therapy, 4, 44.
• Shi Y, Kirwan P and Livesey FJ (2012) Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks. Science Translational Medicine,1836-1846.
• Shi Y, Kirwan P, Smith J, Maclean G, Orkin SH and Livesey FJ (2012) A human stem cell model of early Alzheimerâ€™s disease pathology in Down syndrome.Science Translational Medicine, 124ra29
• Shi Y, Kirwan P, Smith J, Robinson HP and Livesey FJ (2012) Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nature Neuroscience, 15, 477-486