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J. Biol. Chem., Vol. 283, Issue 21, 14751-14761, May 23, 2008

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Processing and Nuclear Localization of CRMP2 during Brain Development Induce Neurite Outgrowth Inhibition^*

Véronique Rogemond, Carole Auger, Pascale Giraudon, Michel Becchi^¶, Nathalie Auvergnon, Marie-Françoise Belin, Jérôme Honnorat¹, and Mahnaz Moradi-Améli²

From the Inserm, U842, Université de Lyon, Lyon 1, UMR-S842, Lyon F-69372, France, Hospices Civils de Lyon, Neurologie B, Bron F-69677, France, and ^¶Institut de Biologie et Chimie des Protéines, CNRS-UMR 5086, Lyon F-69367, France

Collapsin response mediator proteins (CRMPs) are believed to play a crucial role in neuronal differentiation and axonal outgrowth. Among them, CRMP2 mediates axonal guidance by collapsing growth cones during development. This activity is correlated with the reorganization of cytoskeletal proteins. CRMP2 is implicated in the regulation of several intracellular signaling pathways. Two subtypes, A and B, and multiple cytosolic isoforms of CRMP2B with apparent masses between 62 and 66 kDa have previously been reported. Here, we show a new short isoform of 58 kDa, expressed during brain development, derived from C-terminal processing of the CRMP2B subtype. Although full-length CRMP2 is restricted to the cytoplasm, using transfection experiments, we demonstrate that a part of the short isoform is found in the nucleus. Interestingly, at the tissue level, this short CRMP2 is also found in a nuclear fraction of brain extract. By mutational analysis, we demonstrate, for the first time, that nuclear translocation occurs via nuclear localization signal (NLS) within residues Arg⁴⁷¹-Lys⁴⁷² in CRMP2 sequence. The NLS may be unmasked after C-terminal processing; thereby, this motif may be surface-exposed. This short CRMP2 induces neurite outgrowth inhibition in neuroblastoma cells and suppressed axonal growth in cultured cortical neurons, whereas full-length CRMP2 promotes neurite elongation. The NLS-mutated short isoform, restricted to the cytoplasm, abrogates both neurite outgrowth and axon growth inhibition, indicating that short nuclear CRMP2 acts as a dominant signal. Therefore, post-transcriptional processing of CRMP2 together with its nuclear localization may be an important key in the regulation of neurite outgrowth in brain development.

Received for publication, October 11, 2007 , and in revised form, February 28, 2008.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence may be addressed: Inserm U842, Neuro-Oncologie et Neuro-Inflammation, Université de Lyon, Université Lyon 1, Faculté de Médecine Laënnec, Rue Guillaume Paradin, 69372 Lyon cedex 08, France. Tel.: 33-472-35-78-08; Fax: 33-472-35-73-29; E-mail: jerome.honnorat{at}chu-lyon.fr.

² To whom correspondence may be addressed: Inserm U842, Neuro-Oncologie et Neuro-Inflammation, Université de Lyon, Université Lyon 1, Faculté de Médecine Laënnec, Rue Guillaume Paradin, 69372 Lyon cedex 08, France. Tel.: 33-478-78-57-06; Fax: 33-478-77-86-16; E-mail: mahnaz.ameli-moradi{at}univ-lyon1.fr.

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