Cytoplasmic Rbfox1 Regulates the Expression of Synaptic and Autism-Related Genes

Ji Ann Lee, Andrey Damianov, Chia Ho Lin, Mariana Fontes, Neelroop N. Parikshak, Erik S. Anderson, Daniel H. Geschwind, Douglas L. Black, Kelsey C. Martin

Research output: Contribution to journalArticlepeer-review

156 Scopus citations

Abstract

Human genetic studies have identified the neuronal RNA binding protein, Rbfox1, as a candidate gene for autism spectrum disorders. While Rbfox1 functions as a splicing regulator in the nucleus, it is also alternatively spliced to produce cytoplasmic isoforms. To investigate the function of cytoplasmic Rbfox1, we knocked down Rbfox proteins in mouse neurons and rescued with cytoplasmic or nuclear Rbfox1. Transcriptome profiling showed that nuclear Rbfox1 rescued splicing changes, whereas cytoplasmic Rbfox1 rescued changes in mRNA levels. iCLIP-seq of subcellular fractions revealed that Rbfox1 bound predominantly to introns in nascent RNA, while cytoplasmic Rbox1 bound to 3[U+02B9] UTRs. Cytoplasmic Rbfox1 binding increased target mRNA stability and translation, and Rbfox1 and miRNA binding sites overlapped significantly. Cytoplasmic Rbfox1 target mRNAs were enriched in genes involved in cortical development and autism. Our results uncover a new Rbfox1 regulatory network and highlight the importance of cytoplasmic RNA metabolism to cortical development and disease.

Original languageEnglish
Pages (from-to)113-128
Number of pages16
JournalNeuron
Volume89
Issue number1
DOIs
StatePublished - 6 Jan 2016
Externally publishedYes

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