Abstract
Cerebellar granule neurons (CGNs) undergo programmed cell death during the first postnatal week of mouse development, coincident with sustained expression of the death receptor p75NTR. Although ablation of p75NTR does not affect CGN cell death, deletion of the downstream effector RIP2 significantly increases CGN apoptosis, resulting in reduced adult CGN number and impaired behaviors associated with cerebellar function. Remarkably, CGN death is restored to basal levels when p75NTR is deleted in RIP2-deficient mice. We find that RIP2 gates the signaling output of p75NTR by competing with TRAF6 for binding to the receptor intracellular domain. In CGNs lacking RIP2, more TRAF6 is associated with p75NTR, leading to increased JNK-dependent apoptosis. In agreement with this, pharmacological inhibition or genetic ablation of TRAF6 restores cell death levels in CGNs lacking RIP2. These results reveal an unexpected mechanism controlling CGN number and highlight how competitive interactions govern the logic of death receptor function.
Highlights
Death receptors are characterized by the presence of a globular 6-helix bundle domain in their intracellular region known as the ‘‘death domain’’ (Ferrao and Wu, 2012; Park et al, 2007)
We have examined the cerebella of mice lacking RIP2 and found increased Cerebellar granule neurons (CGNs) apoptosis that was mediated by the p75 neurotrophin receptor (p75NTR) death receptor
Re-expression of RIP2 in ripk2À/À mutant neurons by transfection restored cleaved caspase 3 immunoreactivity to wild-type levels (Figure 4C), suggesting that RIP2 can regulate CGN survival cell autonomously. We found that both mature nerve growth factor (NGF) and proNGF were endogenously produced in our CGN cultures and could be detected in CGN supernatants after 1 and 2 DIV (Figure 4D)
Summary
Kisiswa et al report that RIP2 gates the signaling output of p75NTR by competing with TRAF6 for binding to the receptor death domain, increasing the survival of CGN in developing cerebellum. These results reveal a mechanism controlling CGN number and highlight how competitive interactions govern the logic of death receptor function. Highlights d Deletion of RIP2 increased cerebellar granule neuron (CGN) apoptosis through p75NTR d RIP2 mutant mice show reduced CGN density and impaired cerebellar-dependent behavior d RIP2 competes with TRAF6 for binding to p75NTR intracellular domain d RIP2 mutant CGNs have more TRAF6 associated with p75NTR and increased JNK activity.
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