Non-autonomous cell-death is a cardinal feature of the disintegration of neural networks in
neurodegenerative diseases, but the molecular bases of this process are poorly understood. The neural retina comprises a mosaic of rod and cone photoreceptors. Cone and rod photoreceptors degenerate upon rod-specific expression of heterogeneous mutations in functionally distinct genes, whereas cone-specific mutations are thought to cause only cone demise. Here we show that conditional ablation in cone photoreceptors of Ran-binding protein-2 (
Ranbp2), a cell context-dependent pleiotropic
protein linked to neuroprotection, familial necrotic
encephalopathies,
acute transverse myelitis and
tumor-suppression, promotes early electrophysiological deficits, subcellular erosive destruction and non-apoptotic death of cones, whereas rod photoreceptors undergo cone-dependent non-autonomous apoptosis. Cone-specific
Ranbp2 ablation causes the temporal activation of a cone-intrinsic molecular cascade highlighted by the early activation of
metalloproteinase 11/
stromelysin-3 and up-regulation of Crx and CoREST, followed by the down-modulation of cone-specific phototransduction genes, transient up-regulation of regulatory/survival genes and activation of
caspase-7 without apoptosis. Conversely, PARP1+ -apoptotic rods develop upon sequential activation of
caspase-9 and
caspase-3 and loss of membrane permeability. Rod photoreceptor demise ceases upon cone degeneration. These findings reveal novel roles of
Ranbp2 in the modulation of intrinsic and extrinsic cell death mechanisms and pathways. They also unveil a novel spatiotemporal paradigm of progression of neurodegeneration upon cell-specific genetic damage whereby a cone to rod non-autonomous death pathway with intrinsically distinct cell-type death manifestations is triggered by cell-specific loss of
Ranbp2. Finally, this study casts new light onto cell-death mechanisms that may be shared by human dystrophies with distinct
retinal spatial signatures as well as with other etiologically distinct
neurodegenerative disorders.