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The Journal of Neuroscience, October 29, 2003, 23(30):9732-9741

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Development/Plasticity/Repair
Neuronal Migration Depends on Intact Peroxisomal Function in Brain and in Extraneuronal Tissues

Anneleen Janssen,¹ Pierre Gressens,³ Markus Grabenbauer,⁴ Eveline Baumgart,⁴ Arno Schad,⁴ Ilse Vanhorebeek,¹ Annelies Brouwers,¹ Peter E. Declercq,¹ Dariush Fahimi,⁴ Philippe Evrard,³ Luc Schoonjans,⁵ Désiré Collen,⁶ Peter Carmeliet,⁶ Guy Mannaerts,² Paul Van Veldhoven,² and Myriam Baes¹

¹Laboratory of Clinical Chemistry and ²Department of Pharmacology, K. U. Leuven, 3000 Leuven, Belgium, ³Laboratory of Developmental Neurology, Hospital Robert-Debré, 75019 Paris, France, ⁴Department of Anatomy and Cell Biology II, University of Heidelberg, 69117 Heidelberg, Germany, ⁵Thromb-X, 3000 Leuven, Belgium, and ⁶Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, 3000 Leuven, Belgium

Functional peroxisome deficiency, as encountered in Zellweger syndrome, causes a specific impairment of neuronal migration. Although the molecular mechanisms underlying the neuronal migration defect are at present unknown, the excess of very long chain fatty acids in brain, a consequence of peroxisomal-oxidation deficiency, has often been hypothesized to play a major role. The purpose of the present study was to investigate the contribution of peroxisomal dysfunction in brain as opposed to peroxisomal dysfunction in extraneuronal tissues to the migration defect. Peroxisomes were selectively reconstituted either in brain or liver of Pex5 knock-out mice, a model for Zellweger syndrome, by tissue-selective overexpression of Pex5p. We found that both rescue strains exhibited a significant correction of the neuronal migration defect despite an incomplete reconstitution of peroxisomal function in the targeted tissue. Animals with a simultaneous rescue of peroxisomes in both tissues displayed a pattern of neuronal migration indistinguishable from that of wild-type animals on the basis of cresyl violet staining and 5',3'-bromo-2'-deoxyuridine birth-dating analysis. These data suggest that peroxisomal metabolism in brain but also in extraneuronal tissues affects the normal development of the mouse neocortex. In liver-rescued mice, the improvement of the neuronal migration was not accompanied by changes in very long chain fatty acid, docosahexaenoic acid, or plasmalogen levels in brain, indicating that other metabolic factors can influence the neuronal migration process.

Key words: neuronal migration; peroxisome; Zellweger syndrome; VLCFA; plasmalogen; DHA

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Received May 1, 2003; revised August 14, 2003; accepted August 28, 2003.

This article has been cited by other articles:

				M. J. Santos, R. A. Quintanilla, A. Toro, R. Grandy, M. C. Dinamarca, J. A. Godoy, and N. C. Inestrosa Peroxisomal Proliferation Protects from {beta}-Amyloid Neurodegeneration J. Biol. Chem., December 9, 2005; 280(49): 41057 - 41068. [Abstract] [Full Text] [PDF]

				P. Gressens Neuronal Migration Disorders J Child Neurol, December 1, 2005; 20(12): 968 - 971. [Abstract] [PDF]

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