Marose Thomas D, Merkel Calli E, McMahon Andrew P, Carroll Thomas J
Department of Internal Medicine (Nephrology Division), University of Texas Southwestern Medical Center, Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-8856, USA.
Dev Biol. 2008 Feb 1;314(1):112-26. doi: 10.1016/j.ydbio.2007.11.016. Epub 2007 Nov 28.
Differentiation is the process by which tissues/organs take on their final, physiologically functional form. This process is mediated in part by the silencing of embryonic genes and the activation of terminal, differentiation gene products. Mammalian kidney development is initiated when the Wolffian duct branches and invades the overlying metanephric mesenchyme. The newly formed epithelial bud, known as the ureteric bud, will continue to branch ultimately differentiating into the collecting duct system and ureter. Here, we show that Hoxb7-Cre mediated removal of beta-catenin from the mouse Wolffian duct epithelium leads to the premature expression of gene products normally associated with the differentiated kidney collecting duct system including the water channel protein, Aquaporin-3 and the tight junction protein isoform, ZO-1 alpha+. Mutant cells fail to maintain expression of some genes associated with embryonic development, including several mediators of branching morphogenesis, which subsequently leads to kidney aplasia or hypoplasia. Reciprocally, expression of a stabilized form of beta-catenin appears to block differentiation of the collecting ducts. All of these defects occur in the absence of any effects on the adherens junctions. These data indicate a role for beta-catenin in maintaining cells of the Wolffian ducts and the duct derived ureteric bud/collecting duct system in an undifferentiated or precursor state.
分化是组织/器官形成其最终生理功能形式的过程。这个过程部分是由胚胎基因的沉默和终末分化基因产物的激活介导的。当沃尔夫管分支并侵入上方的后肾间充质时，哺乳动物的肾脏发育开始。新形成的上皮芽，即输尿管芽，将继续分支，最终分化为集合管系统和输尿管。在这里，我们表明，Hoxb7-Cre介导的从小鼠沃尔夫管上皮中去除β-连环蛋白会导致通常与分化的肾脏集合管系统相关的基因产物过早表达，包括水通道蛋白Aquaporin-3和紧密连接蛋白异构体ZO-1α+。突变细胞无法维持与胚胎发育相关的一些基因的表达，包括几种分支形态发生的介质，这随后导致肾发育不全或发育不良。相反，稳定形式的β-连环蛋白的表达似乎会阻止集合管的分化。所有这些缺陷都发生在对黏着连接没有任何影响的情况下。这些数据表明β-连环蛋白在维持沃尔夫管细胞以及由该管衍生的输尿管芽/集合管系统处于未分化或前体状态中起作用。
