This study shows that two congenital hydrocephalus (CH)-associated mutations in Trim71 accelerate mouse embryonic stem cells differentiation into neurons; while these mutations reduce binding to known Trim71 target mRNAs, the mutant Trim71s bind new and distinct targets, leading to gain-of-function effects that may contribute to the etiology of CH. Here, TRIM71 is linked to cyclic hematopoiesis.