Non-canonical Ret signaling augments p75-mediated cell death in developing sympathetic neurons

Programmed cell death (PCD) is an evolutionarily conserved process critical in sculpting many organ systems, yet the underlying mechanisms remain poorly understood. Here, we investigated the interactions of pro-survival and pro-apoptotic receptors in PCD using the sympathetic nervous system as a model. We demonstrate that Ret, a receptor tyrosine kinase required for the survival of many neuronal populations, is restricted to a subset of degenerating neurons that rapidly undergo apoptosis. Pro-apoptotic conditions induce Ret to associate with the death receptor p75. Genetic deletion of p75 within Ret(+) neurons, and deletion of Ret during PCD, inhibit apoptosis both in vitro and in vivo. Mechanistically, Ret inhibits nerve growth factor (NGF)–mediated survival of sympathetic neurons. Removal of Ret disrupts NGF-mediated TrkA ubiquitination, leading to increased cell surface levels of TrkA, thereby potentiating survival signaling. Additionally, Ret deletion significantly impairs p75 regulated intramembrane proteolysis cleavage, leading to reduced activation of downstream apoptotic effectors. Collectively, these results indicate that Ret acts non-canonically to augment p75-mediated apoptosis.