title: Netrin-1 acts as a survival factor via its receptors UNC5H and DCC.
abstract: The membrane receptors DCC and UNC5H have been shown to be crucial for axon guidance and neuronal migration by acting as receptors for netrin-1. DCC has also been proposed as a dependence receptor inducing apoptosis in cells that are beyond netrin-1 availability. Here we show that the netrin-1 receptors UNC5H (UNC5H1, UNC5H2, UNC5H3) also act as dependence receptors. UNC5H receptors induce apoptosis, but this effect is blocked in the presence of netrin-1. Moreover, we demonstrate that UNC5H receptors are cleaved in vitro by caspase in their intracellular domains. This cleavage may lead to the exposure of a fragment encompassing a death domain required for cell death induction in vivo. Finally, we present evidence that during development of the nervous system, the presence of netrin-1 is crucial to maintain survival of UNC5H- and DCC-expressing neurons, especially in the ventricular zone of the brainstem. Altogether, these results argue for a role of netrin-1 during the development of the nervous system, not only as a guidance cue but as a survival factor via its receptors DCC and UNC5H.
authors.affiliation: Apoptosis/Differentiation Laboratory-label La Ligue, Molecular and Cellular Genetic Center, CNRS UMR 5534, University of Lyon, 69622 Villeurbanne, France.
authors.forename: F
authors.initials: F
authors.lastname: Llambi
authors.forename: F
authors.initials: F
authors.lastname: Causeret
authors.forename: E
authors.initials: E
authors.lastname: Bloch-Gallego
authors.forename: P
authors.initials: P
authors.lastname: Mehlen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D001933:Brain Stem / Q000166:cytology / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology*; D000075389:DCC Receptor; D017931:DNA Primers; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009414:Nerve Growth Factors / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D000075386:Netrin Receptors; D000075388:Netrin-1; D009474:Neurons / Q000166:cytology / Q000502:physiology; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D025521:Tumor Suppressor Proteins
chemical_list: D020169:Caspases; D015815:Cell Adhesion Molecules; D000075389:DCC Receptor; D017931:DNA Primers; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; D000075388:Netrin-1; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C501909:DCC protein, human; C501910:Dcc protein, mouse; C000617351:NTN1 protein, human; C000617353:Ntn1 protein, mouse; C000617308:Unc5A protein, mouse; C000617307:Unc5b protein, mouse