Yoshino K, Rubin J S, Higinbotham K G, Uren A, Anest V, Plisov S Y, Perantoni A O
Laboratory of Comparative Carcinogenesis, Building 538/Room 205E, National Cancer Institute, Frederick, MD 21702, USA.
Mech Dev. 2001 Apr;102(1-2):45-55. doi: 10.1016/s0925-4773(01)00282-9.
Wnt-4 signaling plays a critical role in kidney development and is associated with the epithelial conversion of the metanephric mesenchyme. Furthermore, secreted Frizzled-related proteins (sFRPs) that can bind Wnts are normally expressed in the developing metanephros, and function in other systems as modulators of Wnt signaling. sfrp-1 is distributed throughout the medullary and cortical stroma in the metanephros, but is absent from condensed mesenchyme and primitive tubular epithelia of the developing nephron where wnt-4 is highly expressed. In contrast, sfrp-2 is expressed in primitive tubules. To determine their role in kidney development, recombinant sFRP-1, sFRP-2 or combinations of both were applied to cultures of 13-dpc rat metanephroi. Both tubule formation and bud branching were markedly inhibited by sFRP-1, but concurrent sFRP-2 treatment restored some tubular differentiation and bud branching. sFRP-2 itself showed no effect on cultures of metanephroi. In cultures of isolated, induced rat metanephric mesenchymes, sFRP-1 blocked events associated with epithelial conversion (tubulogenesis and expression of lim-1, sfrp-2 and E-cadherin); however, it had no demonstrable effect on early events (compaction of mesenchyme and expression of wt1). As shown herein, sFRP-1 binds Wnt-4 with considerable avidity and inhibits the DNA-binding activity of TCF, an effector of Wnt signaling, while sFRP-2 had no effect on TCF activation. These observations suggest that sFRP-1 and sFRP-2 compete locally to regulate Wnt signaling during renal organogenesis. The antagonistic effect of sFRP-1 may be important either in preventing inappropriate development within differentiated areas of the medulla or in maintaining a population of cortical blastemal cells to facilitate further renal expansion. On the other hand, sFRP-2 might promote tubule formation by permitting Wnt-4 signaling in the presence of sFRP-1.
Wnt-4信号通路在肾脏发育中起关键作用，并与后肾间充质的上皮转化相关。此外，能够结合Wnts的分泌型卷曲相关蛋白（sFRPs）通常在后肾发育过程中表达，并在其他系统中作为Wnt信号通路的调节因子发挥作用。sfrp-1分布于后肾的髓质和皮质基质中，但在发育中的肾单位的浓缩间充质和原始肾小管上皮中不存在，而wnt-4在这些部位高度表达。相反，sfrp-2在原始肾小管中表达。为了确定它们在肾脏发育中的作用，将重组sFRP-1、sFRP-2或两者的组合应用于13天龄大鼠后肾培养物中。sFRP-1显著抑制了肾小管形成和芽分支，但同时进行sFRP-2处理可恢复一些肾小管分化和芽分支。sFRP-2本身对后肾培养物没有影响。在分离的、诱导的大鼠后肾间充质培养物中，sFRP-1阻断了与上皮转化相关的事件（肾小管发生以及lim-1、sfrp-2和E-钙黏蛋白的表达）；然而，它对早期事件（间充质致密化和wt1的表达）没有明显影响。如本文所示，sFRP-1以相当高的亲和力结合Wnt-4，并抑制Wnt信号通路的效应器TCF的DNA结合活性，而sFRP-2对TCF激活没有影响。这些观察结果表明，sFRP-1和sFRP-2在肾脏器官发生过程中局部竞争以调节Wnt信号通路。sFRP-1的拮抗作用可能在防止髓质分化区域内的不适当发育或维持皮质胚基细胞群体以促进肾脏进一步扩张方面很重要。另一方面，sFRP-2可能通过在存在sFRP-1的情况下允许Wnt-4信号通路来促进肾小管形成。
