RIP2 Gates TRAF6 Interaction with Death Receptor p75^NTR to Regulate Cerebellar Granule Neuron Survival

Cerebellar granule neurons (CGNs) undergo programmed cell death during the first postnatal week of mouse development, coincident with sustained expression of the death receptor p75^NTR. Although ablation of p75^NTR 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 p75^NTR is deleted in RIP2-deficient mice. We find that RIP2 gates the signaling output of p75^NTR by competing with TRAF6 for binding to the receptor intracellular domain. In CGNs lacking RIP2, more TRAF6 is associated with p75^NTR, 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.