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The Journal of Neuroscience, June 4, 2008, 28(23):5891-5900; doi:10.1523/JNEUROSCI.5187-07.2008

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Cellular/Molecular
Disruption of Krox20–Nab Interaction in the Mouse Leads to Peripheral Neuropathy with Biphasic Evolution

Anne Desmazières,^1,2 Laurence Decker,^1,2 Jean-Michel Vallat,³ Patrick Charnay,^1,2 and Pascale Gilardi-Hebenstreit^1,2

¹Inserm U784, 75230 Paris Cedex 05, France, ²Ecole Normale Supérieure, 75230 Paris Cedex 05, France, and ³Laboratoire de Neurologie, Centre Hospitalier Universitaire Dupuytren, 87402 Limoges, France

Correspondence should be addressed to Patrick Charnay, Inserm U784, 46 rue d'Ulm, 75230 Paris Cedex 05, France. Email: charnay{at}biologie.ens.fr

Krox20/Egr2 is a zinc finger transcription factor that plays essential roles in several developmental processes, including peripheral nervous system myelination by Schwann cells, where it acts as a master gene regulator. Krox20 is known to interact with cofactors of the Nab family and a mutation affecting isoleucine 268, which prevents this interaction, has been shown to result in congenital hypomyelinating neuropathy in humans. To further investigate the role of this interaction, we have introduced such a mutation, Krox20^I268F, in the mouse germ line. Clinical, immunohistochemical, and ultrastructural analyses of the homozygous mutants reveal that they develop a severe hypomyelination phenotype that mimics the human syndrome. Furthermore, a time-course analysis of the disease indicates that it follows a biphasic evolution, the hypomyelination phase being followed by a dramatic demyelination. Although for the regulation of most analyzed Krox20 target genes the mutation behaves as a loss of function, this is not the case for a few of them. This differential effect indicates that the molecular function of the Krox20–Nab interaction is target dependent and might explain the degradation of the residual myelin, because of imbalances in its composition. In conclusion, this work provides a novel and useful model for severe human peripheral neuropathies.

Key words: transcription factor; Charcot–Marie–Tooth disease; animal model; myelin; hindbrain segmentation; cranial ganglia

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Received Nov. 22, 2007; revised March 21, 2008; accepted April 21, 2008.

Correspondence should be addressed to Patrick Charnay, Inserm U784, 46 rue d'Ulm, 75230 Paris Cedex 05, France. Email: charnay{at}biologie.ens.fr

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				M. A. Wassef, D. Chomette, M. Pouilhe, A. Stedman, E. Havis, C. Desmarquet-Trin Dinh, S. Schneider-Maunoury, P. Gilardi-Hebenstreit, P. Charnay, and J. Ghislain Rostral hindbrain patterning involves the direct activation of a Krox20 transcriptional enhancer by Hox/Pbx and Meis factors Development, October 15, 2008; 135(20): 3369 - 3378. [Abstract] [Full Text] [PDF]

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