PUBLICATION
A conserved role for the ALS-linked splicing factor SFPQ in repression of pathogenic cryptic last exons
- Authors
- Gordon, P.M., Hamid, F., Makeyev, E.V., Houart, C.
- ID
- ZDB-PUB-210413-2
- Date
- 2021
- Source
- Nature communications 12: 1918 (Journal)
- Registered Authors
- Houart, Corinne
- Keywords
- none
- MeSH Terms
-
- Amyotrophic Lateral Sclerosis/genetics*
- Animals
- Base Sequence
- Codon, Nonsense*
- Embryo, Nonmammalian/embryology
- Embryo, Nonmammalian/metabolism
- Exons/genetics*
- Gene Expression Regulation, Developmental
- Gene Knockout Techniques
- Humans
- In Situ Hybridization/methods
- Introns/genetics
- Mice
- Neurons/metabolism
- PTB-Associated Splicing Factor/genetics*
- Zebrafish/embryology
- Zebrafish/genetics
- PubMed
- 33771997 Full text @ Nat. Commun.
Citation
Gordon, P.M., Hamid, F., Makeyev, E.V., Houart, C. (2021) A conserved role for the ALS-linked splicing factor SFPQ in repression of pathogenic cryptic last exons. Nature communications. 12:1918.
Abstract
The RNA-binding protein SFPQ plays an important role in neuronal development and has been associated with several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease. Here, we report that loss of sfpq leads to premature termination of multiple transcripts due to widespread activation of previously unannotated cryptic last exons (CLEs). These SFPQ-inhibited CLEs appear preferentially in long introns of genes with neuronal functions and can dampen gene expression outputs and/or give rise to short peptides interfering with the normal gene functions. We show that one such peptide encoded by the CLE-containing epha4b mRNA isoform is responsible for neurodevelopmental defects in the sfpq mutant. The uncovered CLE-repressive activity of SFPQ is conserved in mouse and human, and SFPQ-inhibited CLEs are found expressed across ALS iPSC-derived neurons. These results greatly expand our understanding of SFPQ function and uncover a gene regulation mechanism with wide relevance to human neuropathologies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping