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Molecular and Cellular Biology, November 2003, p. 8233-8245, Vol. 23, No. 22
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.22.8233-8245.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Neurons Expressing the Highest Levels of -Synuclein Are Unaffected by Targeted Inactivation of the Gene

Natalia Ninkina,¹ Katerina Papachroni,^1, Darren C. Robertson,¹ Oliver Schmidt,¹ Liz Delaney,^1, Francis O'Neill,¹ Felipe Court,¹ Arnon Rosenthal,² Susan M. Fleetwood-Walker,¹ Alun M. Davies,¹ and Vladimir L. Buchman^1*

Department of Preclinical Veterinary Sciences, University of Edinburgh, Edinburgh EH9 1QH, United Kingdom,¹ Rinat Neuroscience Corporation, Palo Alto, California 94304²

Received 9 June 2003/ Returned for modification 18 July 2003/ Accepted 14 August 2003

Homologous recombination in ES cells was employed to generate mice with targeted deletion of the first three exons of the -synuclein gene. Complete inactivation of gene expression in null mutant mice was confirmed on the mRNA and protein levels. Null mutant mice are viable, are fertile, and do not display evident phenotypical abnormalities. The effects of -synuclein deficiency on motor and peripheral sensory neurons were studied by various methods in vivo and in vitro. These two types of neurons were selected because they both express high levels of -synuclein from the early stages of mouse embryonic development but later in the development they display different patterns of intracellular compartmentalization of the protein. We found no difference in the number of neurons between wild-type and null mutant animals in several brain stem motor nuclei, in lumbar dorsal root ganglia, and in the trigeminal ganglion. The survival of -synuclein-deficient trigeminal neurons in various culture conditions was not different from that of wild-type neurons. There was no difference in the numbers of myelinated and nonmyelinated fibers in the saphenous nerves of these animals, and sensory reflex thresholds were also intact in -synuclein null mutant mice. Nerve injury led to similar changes in sensory function in wild-type and mutant mice. Taken together, our data suggest that like -synuclein, -synuclein is dispensable for the development and function of the nervous system.

Present address: Department of Biological Chemistry, School of Medicine, University of Athens, 115 27 Athens, Greece.

Present address: Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 2XY, United Kingdom.

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