Abstract
Wilms' tumor 1 (WT1) is essential for the development and homeostasis of multiple mesodermal tissues. Despite evidence for post-transcriptional roles, no endogenous WT1 target RNAs exist. Using RNA immunoprecipitation and UV cross-linking, we show that WT1 binds preferentially to 3' untranslated regions (UTRs) of developmental targets. These target mRNAs are down-regulated upon WT1 depletion in cell culture and developing kidney mesenchyme. Wt1 deletion leads to rapid turnover of specific mRNAs. WT1 regulates reporter gene expression through interaction with 3' UTR-binding sites. Combining experimental and computational analyses, we propose that WT1 influences key developmental and disease processes in part through regulating mRNA turnover.
Highlights
The different steps in gene expression, from transcription through a series of post-transcriptional events, are closely interconnected, and some multifunctional proteins regulate several points in this pathway
The first suggestion that Wilms’ tumor 1 (WT1) may function post-transcriptionally came from Larsson et al (1995), who showed that the +KTS isoforms associate with splicing factors
Further support for post-transcriptional roles for WT1 was provided by Niksic et al (2004), who showed that all isoforms shuttle between the nucleus and cytoplasm, where they are located on actively translating ribosomes
Summary
Transcription factor Wilms’ tumor 1 regulates developmental RNAs through 3′ UTR interaction. Using RNA immunoprecipitation and UV cross-linking, we show that WT1 binds preferentially to 3′ untranslated regions (UTRs) of developmental targets. These target mRNAs are down-regulated upon WT1 depletion in cell culture and developing kidney mesenchyme. Mice lacking Wt1 die at mid-gestation through defective coronary vasculature, suffer from congenital diaphragmatic hernia, and have no kidneys, gonads, spleen, or adrenals All of these defects can be traced to a key role for WT1 in the development of tissues derived from the intermediate and lateral plate mesoderm. This study provides strong evidence that the tumor suppressor protein WT1 regulates physiologically important RNAs and their stability through interactions with 3′ untranslated regions (UTRs)
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