Cell Migration and Morphology
How the billions of neurons within our body find their correct target remains a tantalising mystery but when this goes wrong, congenital conditions such as epilepsy or Down Syndrome result. Rather like trying to mend a computer without knowing how the underlying circuitry was wired up, understanding brain development is therefore essential for devising strategies to repair it after damage or disease.
To form connections, neurons must migrate to their functional place within the brain and extend sinuous protrusions, known as axons, to contact their target. This process requires them to undergo extreme changes in cell shape and execute a series of navigational decisions. These are achieved by the cell's internal protein scaffold which determines its shape and motility in response to a host of external signals. Defects in the scaffold integrity, or its responses to signals, result in defective brain development, impaired neuronal communication or even tumour growth.
The shape of a cell often plays a crucial part in allowing it to function properly. The epitome of this is the nervous system in which neurons send long, sinuous processes to contact other cells and transmit signals. Neurons are dependent upon the support of glial cells which enfold and ensheathe them, providing nutrition and enhancing electrical conduction.
The morphology of neurons and glia changes throughout life in response to environmental signals converging on their internal scaffold, the cytoskeleton. This is a highly dynamic structure which provides both physical support to maintain shape and motile forces to drive changes in morphology and mobility. During embryonic development, many cells of the nervous system must migrate from their place of birth to their functional location. Neurons extend thin processes called axons, often over vast distances relative to the size of the cell, to reach their target nerve or muscle. Schwann cells form extensive sheet-like structures to repeatedly wrap themselves around axons and act like the insulation on a wire. All of these processes must be accurately co-ordinated in both space and time to produce a functional nervous system with all its astonishing complexity.
The task is not finished at birth. Throughout life, the contacts between neurons and glia are constantly being refined, remodelled and replaced. Indeed, the ability to form memories is thought to result from the strengthening or weakening of the contacts between neurons, known as synapses. As we age, the ability to renew synapses appears to diminish, resulting in memory loss and cognitive decline. With the overall ageing of the population, understanding this process is of paramount importance.
Defects within the cytoskeleton - or the signals controlling it - of neurons or glia can lead to a range of disorders, appearing throughout life and resulting in loss of motor or sensory function, epilepsy, memory loss, cognitive impairment or cancer. The aim of the Cell Migration and Morphology group is therefore to understand how human disease and congenital disorders result from a failure to adequately regulate the shape and mobility of cells within the nervous system. This is vital for identifying and pursuing novel therapeutic avenues for many neurological conditions: Motor Neuron disorders (including Spinal Muscular Atrophy, Amyotrophic Lateral Sclerosis and congenital dysinnervation disorders), Parkinson's and Alzheimer's Diseases (for these see also Cellular Signalling and Transport), neuropathies and brain tumors (see also Disorders of Myelinating Cells).
We are an expanding group receiving funding from the UK Research Councils, national medical charities including the Wellcome Trust and local sources such as the Northcott Devon Medical Foundation. We collaborate widely with groups nationally at King's College and University College London, Bristol, Cambridge and York Universities; also internationally in Europe with researchers at the Institut Pasteur in Paris and the University of Ulm in Germany; in the US with colleagues at Harvard Medical School and Colorado State and New York Universities.