A congenital hydrocephalus-causing mutation in Trim71 induces stem cell defects via inhibiting Lsd1 mRNA translation
Qiuying Liu1, Mariah K Novak1, Rachel M Pepin1
1Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
Insights
Mutations in Trim71 cause congenital hydrocephalus (CH) by altering its RNA binding and repressing Lsd1 translation, leading to abnormal neural development. Targeting this mechanism may offer therapeutic potential for CH.
Area of Science:
- Genetics
- Developmental Biology
- Neuroscience
Background:
- Congenital hydrocephalus (CH) is a significant cause of childhood illness.
- Mono-allelic mutations in Trim71, a stem-cell RNA-binding protein, are linked to CH, but the underlying molecular mechanisms are unclear.
Purpose of the Study:
- To elucidate the molecular basis of Trim71-mediated pathogenesis in congenital hydrocephalus.
- To identify the specific molecular targets and pathways affected by CH-associated Trim71 mutations.
Main Methods:
- Utilized mouse embryonic stem cells as a model system.
- Investigated the impact of a specific Trim71 mutation (R783H) on mRNA substrate specificity and protein interactions.
- Assessed the effects of Trim71 mutation on stem cell differentiation and neural lineage commitment.
- Examined the role of Lsd1 (Kdm1a) mRNA regulation by mutant Trim71.
Main Results:
- The R783H mutation in Trim71 altered its mRNA substrate specificity.
- Mutant Trim71 accelerated stem cell differentiation and neural lineage commitment.
- Mutant Trim71, unlike wild-type, bound and repressed the translation of Lsd1 (Kdm1a) mRNA.
- Inhibiting this repression or increasing Lsd1 levels ameliorated the differentiation defects.
Conclusions:
- Identified Lsd1 mRNA as a functionally relevant target of CH-causing Trim71 mutants.
- Provided molecular insights into CH pathogenesis, highlighting aberrant stem cell differentiation and neural commitment.
- Suggests that targeting the Trim71-Lsd1 interaction could be a potential therapeutic strategy for congenital hydrocephalus.
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.
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