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

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

Identifying New Components Participating in the Secondary Cell Wall Formation of Vessel Elements in Zinnia and Arabidopsis[W]

Xylem vessel elements are hollow cellular units that assemble end-to-end to form a continuous vessel throughout the plant body; the xylem vessel is strengthened by the xylem elements' reinforced secondary cell walls (SCWs). This work aims to unravel the contribution of unknown actors in xylem vessel differentiation using the model in vitro cell culture system of Zinnia elegans differentiating cell cultures and the model in vivo system of Arabidopsis thaliana plants. Tracheary Element Differentiation-Related6 (TED6) and TED7 were selected based on an RNA interference (RNAi) screen in the Zinnia system. RNAi reduction of TED6 and 7 delayed tracheary element (TE) differentiation and co-overexpression of TED6 and 7 increased TE differentiation in cultured Zinnia cells. Arabidopsis TED6 and 7 were expressed preferentially in differentiating vessel elements in seedlings. Aberrant SCW formation of root vessel elements was induced by transient RNAi of At TED7 alone and enhanced by inhibition of both TED6 and 7. Protein–protein interactions were demonstrated between TED6 and a subunit of the SCW-related cellulose synthase complex. Our strategy has succeeded in finding two novel components in SCW formation and has opened the door for in-depth analysis of their molecular functions

Altered tau isoform ratio caused by loss of FUS and SFPQ function leads to FTLD-like phenotypes

Fused in sarcoma (FUS) and splicing factor, prolineandglutamine-rich (SFPQ) are RNA binding proteinsthat regulate RNA metabolism. We found that alternativesplicing of the Mapt gene at exon 10, whichgenerates 4-repeat tau (4R-T) and 3-repeat tau(3R-T), is regulated by interactions between FUSand SFPQ in the nuclei of neurons. HippocampusspecificFUS- or SFPQ-knockdown mice exhibitfrontotemporal lobar degeneration (FTLD)-like behaviors,reduced adult neurogenesis, accumulationof phosphorylated tau, and hippocampal atrophywith neuronal loss through an increased 4R-T/3R-Tratio. Normalization of this increased ratio by 4R-Tspecificsilencing results in recovery of the normalphenotype. These findings suggest a biological linkamong FUS/SFPQ, tau isoform alteration, andphenotypic expression, which may function in theearly pathomechanism of FTLD

Altered Tau Isoform Ratio Caused by Loss of FUS and SFPQ Function Leads to FTLD-like Phenotypes

Fused in sarcoma (FUS) and splicing factor, proline- and glutamine-rich (SFPQ) are RNA binding proteins that regulate RNA metabolism. We found that alternative splicing of the Mapt gene at exon 10, which generates 4-repeat tau (4R-T) and 3-repeat tau (3R-T), is regulated by interactions between FUS and SFPQ in the nuclei of neurons. Hippocampus-specific FUS- or SFPQ-knockdown mice exhibit frontotemporal lobar degeneration (FTLD)-like behaviors, reduced adult neurogenesis, accumulation of phosphorylated tau, and hippocampal atrophy with neuronal loss through an increased 4R-T/3R-T ratio. Normalization of this increased ratio by 4R-T-specific silencing results in recovery of the normal phenotype. These findings suggest a biological link among FUS/SFPQ, tau isoform alteration, and phenotypic expression, which may function in the early pathomechanism of FTLD