Highlight Publication March 2008

Donald S, Humby T, Fyfe I, Segonds-Pichon A, Walkers SA, Andrews SR, Coadwell WJ, Emson PC, Wilkinson LS, Welch HCE (2008)
P-Rex2 regulates Purkinje cell dendrite morphology and motor coordination.
Proceedings of the National Academy of Sciences of the United States of America 105 4483-4488
http://dx.doi.org/10.1073/pnas.0712324105

Lay Description

Ataxia is a neurological disorder that is characterised by defects in coordination of certain muscle movements. It can be caused by a number of inherited genetic alterations or through injury and is often associated with a degeneration of the neurons in the cerebellum. The molecular mechanisms that are perturbed in ataxia are complex and still not well-understood.

The small G protein Rac is an important molecular switch inside all cells. It works by integrating the signals it receives from its activators and inhibitors to regulate a wide range of cell functions. It controls, for example, cell shape and motility, gene expression, and free radical formation. For several years, it has been known that artificial manipulations of Rac activity levels in the cerebellum can result in ataxia. However, signalling enzymes that might be physiological activators of Rac in the cerebellum have been unknown until now.

Over the past few years, our lab has studied one particular family of enzymes that activate Rac, the P-Rex family, by looking at the mechanisms that control them and at their functional importance. In this paper, we describe the function of the P-Rex family member P-Rex2 within the brain. We show that, within the brain, P-Rex2 is almost exclusively found within the Purkinje neurons of the cerebellum, cells that are very important for the coordination of movement. We show that Purkinje neurons need P-Rex2 for the correct development of their dendrite structure. We also show that mice which lack the P-Rex2 enzyme (or P-Rex2 plus another family member, P-Rex1) have problems with motor coordination. We conclude that P-Rex1 and P-Rex2 are important regulators of Purkinje cell morphology and cerebellar function. Our next step will be to determine the molecular mechanisms that control the P-Rex/Rac signalling pathway in the Purkinje neuron.

About the Lead Author

Sarah Donald obtained her PhD from the University of Leicester where she investigated the liver toxicity of novel anticancer drugs before joining the Inositide Laboratory at the Babraham Institute as a post doc in 2003. During her time at Babraham, Sarah identified and characterised the enzyme P-Rex2. In this paper, she describes the functional role of P-Rex2 in the cerebellum. Sarah left the Institute at the end of 2007 to take up a research position at Syntaxin Ltd. in Oxford.