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Molecular and Cellular Biology, June 2008, p. 4068-4079, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.02114-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Neogenin Intracellular Domain Regulates Gene Transcription via Nuclear Translocation {triangledown} ,{dagger}

David Goldschneider, Nicolas Rama, Catherine Guix, and Patrick Mehlen*

Apoptosis, Cancer, and Development Laboratory, Equipe Labellisée La Ligue, CNRS UMR5238, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France

Received 28 November 2007/ Returned for modification 19 January 2008/ Accepted 28 March 2008

Neogenin is a multifunctional receptor implicated in axon navigation, neuronal differentiation, morphogenesis, and cell death. Very little is known about signaling downstream of neogenin. Because we found that the neogenin intracellular domain (NeICD) interacts with nuclear proteins implicated in transcription regulation, we investigated further whether neogenin signals similarly to the Notch receptor. We show here that neogenin is cleaved by {gamma}-secretase, an event that releases the complete NeICD. We also describe that NeICD is located at the nucleus, a feature regulated through a balance between nuclear import and export. NeICD triggers gene reporter transactivation and associates with nuclear chromatin. Direct transcriptional targets of NeICD were determined and were shown to be up-regulated in the presence of neogenin ligand. Together, we reveal here a novel aspect of neogenin signaling that relies on the direct implication of its intracellular domain in transcriptional regulation.

* Corresponding author. Mailing address: Apoptosis, Cancer, and Development Laboratory, Equipe Labellisée La Ligue, CNRS UMR5238, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France. Phone: (33) 4 78 78 28 70. Fax: (33) 4 78 78 28 87. E-mail: mehlen{at}lyon.fnclcc.fr

{triangledown} Published ahead of print on 7 April 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, June 2008, p. 4068-4079, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.02114-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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