A Congenital Hydrocephalus-causing Mutation in Trim71 Induces Stem Cell Defects Via Inhibiting Lsd1 mRNA Translation

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2022 Dec 27

PMID 36573342

Authors

Qiuying Liu

Mariah K Novak

Rachel M Pepin

Katharine R Maschhoff

Kailey Worner

Xiaoli Chen

Shaojie Zhang

Wenqian Hu

Affiliations

Soon will be listed here.

Abstract

Congenital hydrocephalus (CH) is a major cause of childhood morbidity. Mono-allelic mutations in Trim71, a conserved stem-cell-specific RNA-binding protein, cause CH; however, the molecular basis for pathogenesis mediated by these mutations remains unknown. Here, using mouse embryonic stem cells as a model, we reveal that the mouse R783H mutation (R796H in human) alters Trim71's mRNA substrate specificity and leads to accelerated stem-cell differentiation and neural lineage commitment. Mutant Trim71, but not wild-type Trim71, binds Lsd1 (Kdm1a) mRNA and represses its translation. Specific inhibition of this repression or a slight increase of Lsd1 in the mutant cells alleviates the defects in stem cell differentiation and neural lineage commitment. These results determine a functionally relevant target of the CH-causing Trim71 mutant that can potentially be a therapeutic target and provide molecular mechanistic insights into the pathogenesis of this disease.

Citing Articles

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A congenital hydrocephalus-causing mutation in Trim71 induces stem cell defects via inhibiting Lsd1 mRNA translation.

Liu Q, Novak M, Pepin R, Maschhoff K, Worner K, Chen X EMBO Rep. 2022; 24(2):e55843.

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