1990年，在10-15%的肾母细胞瘤中发现了编码胚胎肾脏转录因子的WT1基因突变；种系 WT1 突变与涉及肾小球和生殖道发育不良的遗传综合征相关。三十年来，这些发现促使研究人员探索 WT1 的胚胎作用以及 WT1 缺失导致恶性转化的机制。在这里，我们讨论 WT1 的选择性剪接如何产生同种型，这些同种型以特定的方式起作用以激活或抑制靶基因转录。 WT1 还调节转录后调控、改变表观遗传景观并激活 miRNA 表达。 WT1 在肾脏发育的多个阶段发挥作用，包括从静息干细胞到定型肾单位祖细胞的转变，它准备对来自输尿管芽的 WNT9b 信号做出反应。然后，Wt1 通过激活 WNT4 表达并指导肾小球足细胞的发育来驱动肾发生。我们回顾了导致 Denys-Drash、Frasier 和 WAGR 综合征的 WT1 突变。尽管 WT1 的故事始于肾母细胞瘤，但对将异常肾脏发育与恶性转化联系起来的途径的理解仍然存在一些重要差距。肾源性休息中 WT1 的缺失可能会使这些癌前克隆的 DNA 修复酶不足，并可能扰乱表观遗传景观。然而，这些观察结果都没有提供维尔姆斯肿瘤发病机制的完整图景。看来 WT1 的冒险之旅尚未完成，仍有大量未开发的领域有待探索。

In 1990, mutations of the WT1 gene, encoding a transcription factor in embryonic kidney, were found in 10-15% of Wilms tumors; germline WT1 mutations were associated with hereditary syndromes involving glomerular and reproductive tract dysplasia. For >3 decades, these discoveries prompted investigators to explore the embryonic role of WT1 and the mechanisms by which loss of WT1 leads to malignant transformation. Here, we discuss how alternative splicing of WT1 generates isoforms that act in a context-specific manner to activate or repress target gene transcription. WT1 also regulates post-transcriptional regulation, alters the epigenetic landscape and activates miRNA expression. WT1 functions at multiple stages of kidney development, including the transition from resting stem cells to committed nephron progenitor, which it primes to respond to WNT9b signals from ureteric bud. Wt1 then drives nephrogenesis by activating WNT4 expression and directing the development of glomerular podocytes. We review the WT1 mutations that account for Denys-Drash, Frasier and WAGR syndromes. Although the WT1 story began with Wilms tumors, an understanding of the pathways that link aberrant kidney development to malignant transformation still has some important gaps. Loss of WT1 in nephrogenic rests may leave these pre-malignant clones with inadequate DNA repair enzymes and may disturb the epigenetic landscape. Yet none of these observations provide a complete picture of Wilms tumor pathogenesis. It appears that the WT1 odyssey is unfinished and still holds a great deal of untilled ground to be explored.