Rives Anna F, Rochlin Kate M, Wehrli Marcel, Schwartz Stephanie L, DiNardo Stephen
University of Pennsylvania School of Medicine, Department of Cell and Developmental Biology, Philadelphia, PA 190104-6058, USA.
Dev Biol. 2006 May 1;293(1):268-83. doi: 10.1016/j.ydbio.2006.02.006. Epub 2006 Mar 10.
During animal development, Wnt/Wingless (Wg) signaling is required for the patterning of multiple tissues. While insufficient signal transduction is detrimental to normal development, ectopic activation of the pathway can be just as devastating. Thus, numerous controls exist to precisely regulate Wg signaling levels. Endocytic trafficking of pathway components has recently been proposed as one such control mechanism. Here, we characterize the vesicular trafficking of Wg and its receptors, Arrow and DFrizzled-2 (DFz2), and investigate whether trafficking is important to regulate Wg signaling during dorsoventral patterning of the larval wing. We demonstrate a role for Arrow and DFz2 in Wg internalization. Subsequently, Wg, Arrow and DFz2 are trafficked through the endocytic pathway to the lysosome, where they are degraded in a hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs)-dependent manner. Surprisingly, we find that Wg signaling is not attenuated by lysosomal targeting in the wing disc. Rather, we suggest that signaling is dampened intracellularly at an earlier trafficking step. This is in contrast to patterning of the embryonic epidermis, where lysosomal targeting is required to restrict the range of Wg signaling. Thus, signal modulation by endocytic routing will depend on the tissue to be patterned and the goals during that patterning event.
在动物发育过程中，Wnt/Wingless（Wg）信号通路对于多种组织的模式形成是必需的。虽然信号转导不足对正常发育有害，但该通路的异位激活同样具有破坏性。因此，存在许多精确调控Wg信号水平的控制机制。最近有人提出，通路成分的内吞运输是其中一种控制机制。在这里，我们描述了Wg及其受体Arrow和DFrizzled-2（DFz2）的囊泡运输，并研究了在幼虫翅膀的背腹模式形成过程中，运输对于调控Wg信号是否重要。我们证明了Arrow和DFz2在Wg内化中的作用。随后，Wg、Arrow和DFz2通过内吞途径运输到溶酶体，在那里它们以肝细胞生长因子调节的酪氨酸激酶底物（Hrs）依赖的方式被降解。令人惊讶的是，我们发现在翅芽中，Wg信号不会因溶酶体靶向而减弱。相反，我们认为信号在早期运输步骤中在细胞内被减弱。这与胚胎表皮的模式形成相反，在胚胎表皮模式形成中，需要溶酶体靶向来限制Wg信号的范围。因此，通过内吞途径进行的信号调节将取决于要形成模式的组织以及该模式形成事件中的目标。
