LAUSR

The TRIM‐NHL family of proteins shares a conserved domain architecture and play crucial roles in stem cell biology, fertility, and development. This review synthesizes new insights that have revolutionized our understanding of the molecular and biological functions of TRIM‐NHL proteins. Multiple TRIM‐NHLs have been shown to bind specific RNA sequences and structures. X‐ray crystal structures of TRIM‐NHL proteins in complex with RNA ligands reveal versatile modes of RNA recognition by the NHL domain. Functional and genetic analyses show that TRIM‐NHL RNA‐binding proteins negatively regulate the protein expression from the target mRNAs that they bind. This repressive activity plays a crucial role in controlling stem cell fate in the developing brain and differentiating germline. To highlight these paradigms, we focus on several of the most‐extensively studied TRIM‐NHL proteins, specifically Drosophila and vertebrate TRIM71, among others. Brat is essential for development and regulates key target mRNAs to control differentiation of germline and neural stem cells. TRIM71 is also required for development and promotes stem cell proliferation while antagonizing differentiation. Moreover, TRIM71 can be utilized to help reprogram fibroblasts into induced pluripotent stem cells. Recently discovered mutations in TRIM71 cause the neurodevelopmental disease congenital hydrocephalus and emphasize the importance of its RNA‐binding function in brain development. Further relevance of TRIM71 to disease pathogenesis comes from evidence linking it to several types of cancer, including liver and testicular cancer. Collectively, these advances demonstrate a primary role for TRIM‐NHL proteins in the post‐transcriptional regulation of gene expression in crucial biological processes.