Park Joo-Seop, Valerius M Todd, McMahon Andrew P
Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA.
Development. 2007 Jul;134(13):2533-9. doi: 10.1242/dev.006155. Epub 2007 May 30.
Mammalian nephrons form as a result of a complex morphogenesis and patterning of a simple epithelial precursor, the renal vesicle. Renal vesicles are established from a mesenchymal progenitor population in response to inductive signals. Several lines of evidence support the sequential roles of two Wnt family members, Wnt9b and Wnt4, in renal vesicle induction. Using genetic approaches to specifically manipulate the activity of beta-catenin within the mesenchymal progenitor pool in mice, we investigated the potential role of the canonical Wnt pathway in these inductive events. Progenitor-cell-specific removal of beta-catenin activity completely blocked both the formation of renal vesicles and the expected molecular signature of an earlier inductive response. By contrast, activation of stabilized beta-catenin in the same cell population causes ectopic expression of mesenchymal induction markers in vitro and functionally replaces the requirement for Wnt9b and Wnt4 in their inductive roles in vivo. Thus, canonical Wnt signaling is both necessary and sufficient for initiating and maintaining inductive pathways mediated by Wnt9b and Wnt4. However, the failure of induced mesenchyme with high levels of beta-catenin activity to form epithelial structures suggests that modulating canonical signaling may be crucial for the cellular transition to the renal vesicle.
哺乳动物肾单位的形成是一个简单上皮前体——肾小囊进行复杂形态发生和模式形成的结果。肾小囊是由间充质祖细胞群体在诱导信号的作用下形成的。多条证据支持两个Wnt家族成员Wnt9b和Wnt4在肾小囊诱导过程中的相继作用。我们利用基因方法特异性地操纵小鼠间充质祖细胞库中β-连环蛋白的活性，研究了经典Wnt信号通路在这些诱导事件中的潜在作用。在祖细胞中特异性去除β-连环蛋白活性完全阻断了肾小囊的形成以及早期诱导反应预期的分子特征。相比之下，在同一细胞群体中激活稳定的β-连环蛋白会在体外导致间充质诱导标志物的异位表达，并在功能上替代体内Wnt9b和Wnt4在其诱导作用中的需求。因此，经典Wnt信号对于启动和维持由Wnt9b和Wnt4介导的诱导通路既是必要的也是充分的。然而，具有高水平β-连环蛋白活性的诱导间充质未能形成上皮结构，这表明调节经典信号对于细胞向肾小囊的转变可能至关重要。
