Congenital hydrocephalus (CH) is a common neurological disorder affecting many newborns. Imbalanced neurogenesis is a major cause of CH. Multiple CH-associated mutations are within the RNA-binding domain of Trim71, a conserved, stem cell-specific RNA-binding protein. How these mutations alter stem cell fate is unclear. Here, we show that the CH-associated mutations R595H and R783H in Trim71 accelerate differentiation and enhance neural lineage commitment in mouse embryonic stem cells (mESCs), and reduce binding to mRNAs targeted by wild-type Trim71, consistent with previous reports. Unexpectedly, however, each mutant binds an ectopic and distinct repertoire of target mRNAs. R595H-Trim71, but not R783H-Trim71 nor wild-type Trim71, binds the mRNA encoding β-catenin and represses its translation. Increasing β-catenin by overexpression or treatment with a Wnt agonist specifically restores differentiation of R595H-Trim71 mESCs. These results suggest that Trim71 mutations give rise to unique gain-of-function pathological mechanisms in CH. Further, our studies suggest that disruption of the Wnt/β-catenin signaling pathway can be used to stratify disease etiology and develop precision medicine approaches for CH.
Copyright: © 2023 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.