Yu T, Scully S, Yu Y, Fox G M, Jing S, Zhou R
Laboratory for Cancer Research, Department of Chemical Biology, College of Pharmacy, Rutgers University, Piscataway, New Jersey 08855, USA.
J Neurosci. 1998 Jun 15;18(12):4684-96. doi: 10.1523/JNEUROSCI.18-12-04684.1998.
Glial cell line-derived neurotrophic factor (GDNF) and a related factor, neurturin, promote survival of diverse groups of neurons. Both GDNF and neurturin signal via a two-component receptor complex that consists of a ligand-binding GDNF family receptor (GFRalpha-1 or GFRalpha-2) and the receptor protein tyrosine kinase Ret. Recently, a third receptor related to GFRalpha-1 and GFRalpha-2 has also been isolated and designated GFRalpha-3. Although much is known about the interaction among GDNF family factors, Ret, and the alpha-receptors in vitro, it remains unclear about their interactions in vivo. We show here by in situ hybridization that Ret and the alpha-receptors may be colocalized in the same tissues or expressed separately in projecting and target tissues, respectively, indicating that two distinct modes of interaction between Ret and the alpha-receptors exist in vivo. First, Ret may interact with the alpha-receptors expressed in the same cells (termed interaction "in cis") in many tissues and cell populations that respond to GDNF and/or neurturin, such as the substantia nigra, dorsal root ganglia, spinal cord motoneurons, kidney, and intestine. Second, Ret may interact with the alpha-receptors localized in the target neurons (termed interaction "in trans"). In addition, we present evidence in vitro that GFRalpha-1 mediates Ret activation by GDNF in trans. These observations suggest that there are multiple mechanisms regulating the interaction between Ret and the alpha-receptors that mediates the effects of GDNF family trophic factors on the survival and differentiation of cells and on neuron-target interactions in the nervous system.
胶质细胞系源性神经营养因子（GDNF）和一种相关因子——神经营养素，可促进多种神经元的存活。GDNF和神经营养素均通过一种双组分受体复合物进行信号传导，该复合物由一个配体结合型GDNF家族受体（GFRα-1或GFRα-2）和受体蛋白酪氨酸激酶Ret组成。最近，一种与GFRα-1和GFRα-2相关的第三种受体也已被分离出来，并命名为GFRα-3。尽管关于GDNF家族因子、Ret和α受体在体外的相互作用已了解很多，但它们在体内的相互作用仍不清楚。我们在此通过原位杂交表明，Ret和α受体可能在同一组织中共定位，或分别在投射组织和靶组织中表达，这表明Ret和α受体在体内存在两种不同的相互作用模式。首先，Ret可能与在许多对GDNF和/或神经营养素产生反应的组织和细胞群体（如黑质、背根神经节、脊髓运动神经元、肾脏和肠道）中同一细胞内表达的α受体相互作用（称为“顺式”相互作用）。其次，Ret可能与位于靶神经元中的α受体相互作用（称为“反式”相互作用）。此外，我们在体外提供证据表明，GFRα-1介导GDNF对Ret的反式激活。这些观察结果表明，存在多种机制调节Ret与α受体之间的相互作用，这种相互作用介导了GDNF家族营养因子对细胞存活和分化以及神经系统中神经元-靶标相互作用的影响。
