Stromal beta-catenin activation impacts nephron progenitor differentiation in the developing kidney and may contribute to Wilms tumor. Stromal beta-catenin activation impacts nephron progenitor differentiation in the developing kidney and may contribute to Wilms tumor

Wilms tumor (WT) morphologically resembles the embryonic kidney, consisting of blastema, epithelial, and stromal components, suggesting tumors arise from the dysregulation of normal development. Activation of beta-catenin is observed in a significant proportion of human WTs; however, much remains to be understood about how it contributes to tumorigenesis. While activating beta-catenin mutations are observed in both blastema and stromal components of human WT, current models assume that activation in the blastemal lineage is causal. Paradoxically, studies performed in mice suggest that activation of b-catenin in this lineage results in loss of nephron progenitor cell (NPC) renewal, a phenotype opposite to WT. Here, we show that activation of beta-catenin in the stromal lineage acts non-autonomously, resulting in expansion of NPCs and an inhibition of differentiation. Comparisons of the transcriptomes of kidneys expressing an activated allele of beta-catenin in the stromal or nephron progenitor cells reveals that human WT more closely resembles the stromal-lineage mutants. These findings suggest that stromal beta-catenin activation results in histological and molecular features of human WT, providing insights into how stroma signaling may play an active role in tumorigenesis. Overall design: Mouse models with activated beta-catenin specifically in the nephron progenitor or stromal lineages were generated by crossing mice carrying an inducibly activated allele of beta-catenin (CTNNB1 ex3/+) to mice expressing Cre in nephron progenitor (Six2Cre) or the stroma (Foxd1Cre) cell lineages.

肾母细胞瘤（Wilms tumor, WT）在形态学上与胚胎肾脏相似，由胚基、上皮及间质三种成分构成，提示该肿瘤起源于正常发育过程的失调。β-连环蛋白（beta-catenin）的激活在相当比例的人类WT中被检测到，但关于其如何参与肿瘤发生仍有诸多机制有待阐明。尽管人类WT的胚基与间质成分中均存在激活型β-连环蛋白突变，现有模型均认为胚系谱系中的β-连环蛋白激活是致病的关键诱因。矛盾的是，现有小鼠研究显示，该谱系中β-连环蛋白的激活会导致肾单位祖细胞（nephron progenitor cell, NPC）更新能力丧失，这一表型与WT的病理特征恰好相反。本研究证实，间质谱系中的β-连环蛋白激活可通过非细胞自主方式发挥作用，促使肾单位祖细胞扩增并抑制其分化。对在间质或肾单位祖细胞中携带激活型β-连环蛋白等位基因的小鼠肾脏转录组进行比较分析后发现，人类WT的转录谱更接近间质谱系突变体的转录特征。上述研究结果表明，间质β-连环蛋白激活可重现人类WT的组织学与分子特征，为理解间质信号如何主动参与肿瘤发生提供了全新视角。总体实验设计：通过将携带诱导型激活型β-连环蛋白等位基因（CTNNB1 ex3/+）的小鼠，分别与在肾单位祖细胞（Six2Cre）或间质细胞（Foxd1Cre）谱系中表达Cre重组酶的小鼠杂交，构建了仅在肾单位祖细胞或间质谱系中存在β-连环蛋白激活的小鼠模型。