Cis and trans RET signaling control the survival and central projection growth of rapidly adapting mechanoreceptors.
Cis and trans RET signaling control the survival and central projection growth of rapidly adapting mechanoreceptors.
复制标题
作者：
Fleming MS;Vysochan A;Paixão S;Niu J;Klein R;Savitt JM;Luo W
RET在体外可被其共受体和配体顺式或反式激活，但反式信号转导的生理作用尚不清楚。背根神经节（DRG）中的快速适应（RA）机械感受器表达Ret和辅助受体Gfrα2，并依赖于Ret的存活和中央突起生长。在这里，我们发现Ret和Gfrα2基因敲除小鼠表现出相当的早期中枢投射缺陷，但Gfrα2基因敲除的RA机械感受器恢复较晚。Gfrα1（参与激活反式RET的辅助受体）的缺失不会导致显著的中枢投射或细胞存活缺陷，但Gfrα1;Gfrα2双重无效表型Ret无效。最后，我们证明了邻近DRG神经元产生的GFRα1激活RA机械感受器中的RET。总之，我们的研究结果表明，反式和顺式RET信号可以在相同的发育过程中发挥作用，这两种形式的激活可能会增强，但不会多样化RET信号的结果。DOI：http://dx.doi.org/10.7554/eLife.06828.001在发育过程中，细胞发送和接收许多信号分子。为了触发生物反应，这些信号分子必须首先与通常位于细胞表面的特定受体蛋白结合。这些受体蛋白可以单独工作，也可以与称为辅助受体的伴侣蛋白一起工作。当辅助受体由与受体相同的细胞产生时，它被称为顺式信号传导。当辅助受体由其他细胞产生时，它被称为反式信号传导。RET是一种这样的受体，对神经系统和许多其他生物过程的发育很重要。它与特定的信号分子家族（胶质细胞系源性神经营养因子（GDNF）家族配体）相互作用，在与RET结合之前，GDNF家族配体首先与辅助受体GFRα结合。这些共受体可以来自与RET相同的细胞，也可以来自不同的细胞。先前的研究表明，RET可以使用培养的细胞接收顺式和反式信号，但尚不清楚这两种类型的信号是否发生在正常发育过程中，并有助于相同的生物过程。Fleming，Vysochan等人通过分析RET信号在一种参与感知触摸的小鼠神经元中的作用来研究这个问题。RET对于这些神经元的存活和发育是重要的，这些神经元表达RET及其共受体GFRa 2。另一种RET辅助受体GFRa 1是由靠近这些触觉神经元的细胞体和投射的其他细胞产生的。为了进一步研究不同GFRa共受体的作用，Fleming，Vysochan等人产生了多种小鼠突变体，包括在一种或两种类型的共受体中具有突变的小鼠。缺乏这两种辅助受体的小鼠神经元与缺乏RET的小鼠神经元具有相同的缺陷。任何一种辅助受体的单独缺失都不会产生这些异常。这表明两种辅助受体都可以介导这些神经元的正常发育，GFRa 2信号传导为顺式，GFRa 1信号传导为反式。Fleming，Vysochan等人提出，顺式和反式RET信号传导可以在这些神经元中导致相同的生物学结果。未来的实验应该揭示顺式和反式RET信号是否也有助于体内其他细胞类型的共同生物学过程。这些发现对于理解RET信号在癌症和其他人类疾病中的作用也很重要。DOI：http://dx.doi.org/10.7554/eLife.06828.002网站
RET can be activated in cis or trans by its co-receptors and ligands in vitro, but the physiological roles of trans signaling are unclear. Rapidly adapting (RA) mechanoreceptors in dorsal root ganglia (DRGs) express Ret and the co-receptor Gfrα2 and depend on Ret for survival and central projection growth. Here, we show that Ret and Gfrα2 null mice display comparable early central projection deficits, but Gfrα2 null RA mechanoreceptors recover later. Loss of Gfrα1, the co-receptor implicated in activating RET in trans, causes no significant central projection or cell survival deficit, but Gfrα1;Gfrα2 double nulls phenocopy Ret nulls. Finally, we demonstrate that GFRα1 produced by neighboring DRG neurons activates RET in RA mechanoreceptors. Taken together, our results suggest that trans and cis RET signaling could function in the same developmental process and that the availability of both forms of activation likely enhances but not diversifies outcomes of RET signaling. DOI: http://dx.doi.org/10.7554/eLife.06828.001 During development, cells send and receive numerous signaling molecules. In order to trigger a biological response, such signaling molecules must first bind to a specific receptor protein, often located on the cell surface. These receptor proteins can either work alone or with partner proteins called co-receptors. When the co-receptor is produced by the same cell as the receptor, it is called cis signaling. When the co-receptor is produced by other cells, it is called trans signaling. RET is one such receptor that is important for the development of the nervous system and many other biological processes. It interacts with a particular family of signaling molecules, the glial cell line-derived neurotrophic factor (GDNF) family ligands, which first bind to a co-receptor, GFRα, before binding to RET. These co-receptors can come from the same cell as RET, or from a different cell. Previous studies have indicated that RET can receive both cis and trans signals using cultured cells, but it was not clear whether both types of signal occur during normal development and contribute to the same biological processes. Fleming, Vysochan et al. investigated this question by analyzing the roles of RET signaling in a type of mouse neuron that is involved in sensing touch. RET is important for the survival and development of these neurons, which express both RET and its co-receptor GFRa2. Another RET co-receptor, GFRa1, is produced by other cells that are next to the cell bodies and projections of these touch-sensing neurons. To investigate the roles of different GFRa co-receptors further, Fleming, Vysochan et al. generated a variety of mouse mutants, including mice with mutations in one or both types of co-receptor. The neurons in mice lacking both co-receptors shared the same defects as the neurons in the mice lacking RET. Loss of either co-receptor alone did not produce these abnormalities. This indicates that both co-receptors can mediate the normal development of these neurons, with GFRa2 signaling in cis and GFRa1 signaling in trans. Fleming, Vysochan et al. propose that cis and trans RET signaling can lead to the same biological outcomes in these neurons. Future experiments should reveal if cis and trans RET signaling contribute towards common biological processes in other cell types inside the body as well. Such findings might also be important for understanding the role of RET signaling in cancer and other human diseases. DOI: http://dx.doi.org/10.7554/eLife.06828.002