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 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, using mouse as a model system.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, including microRNAs and the polycomb chromatin-modifying complexes. In the other major strand of research in the group, we have used our understanding of murine cortical stem cells to develop methods for directing differentiation of human pluripotent stem cells to cortical neurons, via a cortical stem cell stage.We are using this system for basic studies of human cortical neurogenesis and to generate models of cortical diseases, with an initial focus on Down syndrome and Alzheimer’s disease.

Layer-specific gene expression in neurons of different layers (red, green and yellow) of the cerebral cortex

A human cortical neural stem cell rosette, with stem cells (red) dividing at the apical surface (green).

Plain English:
Making a brain depends on producing all of the different types of nerve cells in the correct places and at the appropriate times before wiring those nerve cells together to make functional circuits. We study how neural stem and progenitor cells build the executive centre of the mammalian brain, the neocortex. The neocortex is the part of the front of the brain that mammals, including humans, use to perceive physical sensations, sound and vision and where thoughts are generated and movement initiated. The consequences of mis-wiring in the cortex are neurological disease and disability, ranging from epilepsy to autism to major learning disabilities. An understanding of how stem and progenitor cells build the cortex is essential for understanding these neurodevelopmental disorders and also for the development of stem cell-based therapies for neurological repair. The cortex is a mammal-specific structure, so we also think that studying how genes are used to build the cortex will help us understand the evolution of uniquely human abilities, such as language.

Selected publications:

• 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 Natl Acad Sci USA 107, 15957-15962.

• Andersson T, Rahman S, Sansom SN, Alsio JM, Kaneda M, Smith J, O’Carroll D,Tarakhovsky A and Livesey FJ (2010) Reversible block of mouse neural stem cell differentiation in the absence of dicer and microRNAs PLoS ONE 5, e13453

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

• Sansom SN, Griffiths DS, Faedo A, Kleinjan DJ, Ruan Y, Smith J, van Heyningen V, Rubenstein JL and Livesey FJ (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

• Sansom SN and Livesey FJ (2009) Gradients in the brain: the control of the development of form and function in the cerebral cortex Cold Spring Harb Perspect Biol 1:a002519

Human stem cell-derived neuropithelial rosettes expressing cerebral cortex transcription factors

A single astrocyte (red) in a culture of human cortical neurons (green).