A p75/Ret receptor complex as an integrator for survival and death

 描述(申请人提供)：在发育中的神经系统中，多余的神经元被产生，这些神经元是不必要的，或者是不适当的连接，并通过程序性细胞死亡来消除。在外周神经细胞群体中，细胞凋亡的程度既由神经支配目标提供的有限的促进生存的神经营养因子供应，也由成功竞争神经营养因子的神经元分泌的诱导凋亡的竞争因子决定。神经营养因子家族中最常见的一类是胶质细胞系源性神经营养因子(GDNF)家族配体，它支持自主神经、体感和脊髓运动神经元的存活和轴突引导。最近我们发现，它们共同的信号转导受体酪氨酸激酶(Ret)的GFL激活，导致Ret与交感神经元和感觉神经元中死亡受体家族成员p75的联系。重要的是，我们发现p75对于GFL介导的Ret的激活和感觉神经元的存活是至关重要的。值得注意的是，我们还发现，在BDNF刺激交感神经元时，Ret与p75相互作用，从而触发这些神经元的凋亡性死亡。RET缺失可抑制BDNF诱导的交感神经元凋亡。我们的主要假设是，p75-Ret受体复合体是一个调节生存和凋亡的开关，取决于哪种配体促进了该复合体的组装，并整合了一致的生存和死亡信号。这个应用程序的目标有两个：(1)检验假设 P75对于GFL介导的伤害性神经元的存活至关重要；(2)检验Ret对交感神经元中死亡受体p75的凋亡功能是必需的假设。为了实现这些目标，我们将在原代神经元和转基因小鼠中结合使用生化和细胞生物学技术。这些实验对于描绘神经营养因子和竞争因子相互对立的作用塑造周围感觉和自主神经回路的分子机制至关重要。此外，确定这些在生存和死亡之间创造平衡的受体机制将使开发神经系统损伤和疾病的治疗策略成为一种更合理的方法。

 DESCRIPTION (provided by applicant): In the developing nervous system, excess neurons are generated which are nonessential, or inappropriately connected, and are eliminated by programmed cell death. In peripheral neuronal populations, the extent of apoptosis is governed by both a limited supply of survival-promoting neurotrophic factors supplied by targets of innervation and by apoptosis-inducing competition factors secreted by neurons that successfully compete for neurotrophic factors, or "winning neurons." One of the prevalent families of neurotrophic factors is the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), which support the survival and axon guidance of autonomic, somatosensory and spinal motor neurons. Recently we have discovered that GFL activation of their common signal transducing receptor tyrosine kinase, Ret, causes the association of Ret with p75, a member of the TNF family of death receptors, in sympathetic and sensory neurons. Importantly, we discovered that p75 was critical for GFL-mediated activation of Ret and survival of sensory neurons in vitro. Remarkably, we also found that Ret interacts with p75 upon BDNF stimulation of sympathetic neurons, which triggers the apoptotic death of these neurons. Ret deletion impaired BDNF-induced apoptosis of sympathetic neurons. Our overarching hypothesis is that the p75-Ret receptor complex is a switch regulating survival and apoptosis, depending upon which ligand promotes the assembly of this complex, and serves to integrate coincident survival and death signals. The objectives of this application are two-fold: (1) to test the hypothesis that p75 is critical for the GFL-mediated survival of nociceptive neurons; (2) to test the hypothesis that Ret is necessary for the apoptotic function of the death receptor p75 in sympathetic neurons. In order to accomplish these objectives we will use a combination of biochemical and cell biological techniques in primary neurons and transgenic mice. These experiments are critical for delineating the molecular mechanisms by which the opposing actions of neurotrophic factors and competition factors sculpt peripheral sensory and autonomic circuits. Furthermore, the determination of these receptor mechanisms that create an equilibrium between survival and death will enable a more rational approach for the development of therapeutic strategies for nervous system injuries and diseases.