The RNA-binding protein TRIM71 as a regulator of renal development

• Applicant: Dr. Thomas Welte
• Subject Area: Nephrology ; Developmental Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 466417053

Faithful development relies on a balance between self-renewal and differentiation of stem cells and their progeny. This requires precise control of gene expression programs. The phylogenetically conserved RNA binding protein and ubiquitin ligase TRIM71 plays a central role in regulating cell differentiation and proliferation in stem cells. Despite being an essential regulator of development, the molecular mechanisms and specific function of TRIM71 in mammalian development are not well characterized. Our previous work has demonstrated that Trim71’s function as an RNA binding protein is critical for its role in regulating stem cell fates. Our analysis showed that TRIM71 recognizes its RNA targets by binding to hairpin motifs in 3’ untranslated regions of target genes, leading to their degradation. The molecular machineries mediating this function remain to be characterized. To uncover these factors, we performed a reporter-based genetic screen in mouse embryonic stem cells. This identified candidate genes that modulate TRIM71 activity directly (co-factors), or indirectly (up-stream regulators). We will focus on co-factor candidates, which will be validated by interaction assays, followed by functional testing using established reporter-gene assays and endogenous RNA targets. Having gained a detailed understanding of TRIM71’s functions, we will focus on TRIM71’s role in mammalian development. Although its functions in mammalian development are still poorly understood, TRIM71’s role in timing worm development is well characterized. Hence, manipulating its levels in mammalian development might prolong, or precociously terminate developmental programs, making it an interesting candidate for regenerative and cancer medicine. As both TRIM71 up-stream regulators, and down-stream RNA targets have been implicated in nephrogenesis and kidney cancer, and preliminary results in zebrafish suggest the same function for TRIM71, we will focus on characterizing its function in kidney development. Specifically, we will generate conditional knock-out and over-expression mouse models to introduce kidney-specific and temporal perturbations of TRIM71 expression. These mouse models will be utilized to study the effect of TRIM71 deletion and overproduction on kidney development. In summary, this research project will identify the molecular machineries and specific functions of TRIM71 in mammalian kidney development, providing a comprehensive analysis of this important regulator of development.

• DFG Programme: Research Grants
• International Connection: Switzerland
• Cooperation Partner: Dr. Helge Grosshans