Cell Reports
Volume 24, Issue 4, 24 July 2018, Pages 1013-1024
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Article
RIP2 Gates TRAF6 Interaction with Death Receptor p75NTR to Regulate Cerebellar Granule Neuron Survival

https://doi.org/10.1016/j.celrep.2018.06.098Get rights and content
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Highlights

  • Deletion of RIP2 increased cerebellar granule neuron (CGN) apoptosis through p75NTR

  • RIP2 mutant mice show reduced CGN density and impaired cerebellar-dependent behavior

  • RIP2 competes with TRAF6 for binding to p75NTR intracellular domain

  • RIP2 mutant CGNs have more TRAF6 associated with p75NTR and increased JNK activity

Summary

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.

Keywords

cell death
NGF
development
cerebellum

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4

Present address: IMP Research Institute of Molecular Pathology, Vienna, Austria

5

Lead Contact