The Neogenin Intracellular Domain Regulates Gene Transcription via Nuclear Translocation

Apoptosis, Cancer and Development Laboratory- Equipe labellisée ‘La Ligue’, CNRS UMR5238, Université de Lyon, Centre Léon Bérard, 69008 Lyon. France

^* To whom correspondence should be addressed. Email: mehlen{at}lyon.fnclcc.fr.

	Abstract

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 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 -secretase, an event that releases the complete neogenin intracellular domain (NeICD). We also describe that NeICD is located to 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 upon neogenin ligand presence. Together, we reveal here a novel aspect of neogenin signaling that relies on the direct implication of its intracellular domain in transcriptional regulation.