RRC ID 63141
Author Yanaizu M, Washizu C, Nukina N, Satoh JI, Kino Y.
Title CELF2 regulates the species-specific alternative splicing of TREM2.
Journal Sci Rep
Abstract Genetic variations of TREM2 have been implicated as a risk factor of Alzheimer's disease (AD). Recent studies suggest that the loss of TREM2 function compromises microglial responses to the accumulation of amyloid beta. Previously, we found that exon 3 of TREM2 is an alternative exon whose skipping leads to a reduction in full-length TREM2 protein by inducing nonsense-mediated mRNA decay. Here, we aimed to identify factors regulating TREM2 splicing. Using a panel of RNA-binding proteins, we found that exon 3 skipping of TREM2 was promoted by two paralogous proteins, CELF1 and CELF2, which were both linked previously with risk loci of AD. Although the overexpression of both CELF1 and CELF2 enhanced exon 3 skipping, only CELF2 reduced the expression of full-length TREM2 protein. Notably, the TREM2 ortholog in the green monkey, but not in the mouse, showed alternative splicing of exon 3 like human TREM2. Similarly, splicing regulation of exon 3 by CELF1/2 was found to be common to humans and monkeys. Using chimeric minigenes of human and mouse TREM2, we mapped a CELF-responsive sequence within intron 3 of human TREM2. Collectively, our results revealed a novel regulatory factor of TREM2 expression and highlighted a species-dependent difference of its regulation.
Volume 10(1)
Pages 17995
Published 2020-10-22
DOI 10.1038/s41598-020-75057-x
PII 10.1038/s41598-020-75057-x
PMID 33093587
PMC PMC7582162
MeSH Alternative Splicing* Animals CELF Proteins / genetics CELF Proteins / metabolism* Exons* Gene Expression Regulation* HEK293 Cells Humans Membrane Glycoproteins / genetics* Membrane Glycoproteins / metabolism Mice Nerve Tissue Proteins / genetics Nerve Tissue Proteins / metabolism* Receptors, Immunologic / genetics* Receptors, Immunologic / metabolism Species Specificity
IF 3.998
Human and Animal Cells 293(RCB1637) HeLa(RCB0007) THP-1(RCB1189)