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

Programmed cell death is a critical process in sculpting the developing nervous system, but the underlying signaling mechanisms remain poorly defined. Donnelly et al. demonstrate a non-canonical function for the neurotrophic factor receptor Ret in p75-mediated apoptosis in 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.

程序性细胞死亡是塑造发育中的神经系统的关键过程，但其潜在的信号传导机制仍不明确。唐纳利等人证明了神经营养因子受体Ret在交感神经元中p75介导的细胞凋亡中具有非经典功能。 程序性细胞死亡（PCD）是一种在进化上保守的过程，对塑造许多器官系统至关重要，然而其潜在机制仍知之甚少。在此，我们以交感神经系统为模型研究了PCD中促存活和促凋亡受体的相互作用。我们证明，Ret是一种受体酪氨酸激酶，对许多神经元群体的存活是必需的，它局限于快速发生凋亡的退化神经元的一个子集。促凋亡条件诱导Ret与死亡受体p75结合。在Ret⁺神经元中p75的基因缺失，以及在PCD过程中Ret的缺失，在体外和体内都抑制细胞凋亡。从机制上讲，Ret抑制神经生长因子（NGF）介导的交感神经元的存活。Ret的缺失破坏了NGF介导的TrkA泛素化，导致TrkA的细胞表面水平升高，从而增强存活信号。此外，Ret的缺失显著损害p75调节的膜内蛋白水解切割，导致下游凋亡效应因子的激活减少。总之，这些结果表明Ret以非经典方式发挥作用，增强p75介导的细胞凋亡。