3′UTR Length-Dependent Control of SynGAP Isoform α2 mRNA by FUS and ELAV-like Proteins Promotes Dendritic Spine Maturation and Cognitive Function

Satoshi Yokoi, Tsuyoshi Udagawa, Yusuke Fujioka, Daiyu Honda, Haruo Okado, Hirohisa Watanabe, Masahisa Katsuno, Shinsuke Ishigaki, Gen Sobue

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

FUS is an RNA-binding protein associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Previous reports have demonstrated intrinsic roles of FUS in synaptic function. However, the mechanism underlying FUS's regulation of synaptic morphology has remained unclear. We found that reduced mature spines after FUS depletion were associated with the internalization of PSD-95 within the dendritic shaft. Mass spectrometry of PSD-95-interacting proteins identified SynGAP, whose expression decreased after FUS depletion. Moreover, FUS and the ELAV-like proteins ELAVL4 and ELAVL1 control SynGAP mRNA stability in a 3′UTR length-dependent manner, resulting in the stable expression of the alternatively spliced SynGAP isoform α2. Finally, abnormal spine maturation and FTLD-like behavioral deficits in FUS-knockout mice were ameliorated by SynGAP α2. Our findings establish an important link between FUS and ELAVL proteins for mRNA stability control and indicate that this mechanism is crucial for the maintenance of synaptic morphology and cognitive function. Yokoi et al. show that FUS, a causative protein of FTLD/ALS, regulates the expression of SynGAP isoform α2, which is critical for spine maturation and cognitive behavior. FUS and ELAVL proteins cooperatively control SynGAP mRNA stability at its 3′UTR, resulting in specific SynGAP isoform expression in a 3′UTR length-dependent manner.

Original languageEnglish
Pages (from-to)3071-3084
Number of pages14
JournalCell Reports
Volume20
Issue number13
DOIs
Publication statusPublished - 26-09-2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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