Netrin-1 acts as a survival factor via its receptors UNC5H and DCC.
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.
Llambi
F
F
Apoptosis/Differentiation Laboratory-label La Ligue, Molecular and Cellular Genetic Center, CNRS UMR 5534, University of Lyon, 69622 Villeurbanne, France.
Causeret
F
F
Bloch-Gallego
E
E
Mehlen
P
P
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
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