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

doi:10.1016/j.neuron.2015.11.025

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

Neuron. 2016 Jan 6;89(1):113-28. doi: 10.1016/j.neuron.2015.11.025. Epub 2015 Dec 10.

Authors

Ji-Ann Lee¹, Andrey Damianov², Chia-Ho Lin², Mariana Fontes¹, Neelroop N Parikshak³, Erik S Anderson², Daniel H Geschwind³, Douglas L Black⁴, Kelsey C Martin⁵

Affiliations

¹ Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: kcmartin@mednet.ucla.edu.

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' 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media

MeSH terms

Alternative Splicing / genetics
Animals
Autistic Disorder / genetics*
Brain / growth & development
Brain / metabolism
Cytoplasm / metabolism
Estriol / analogs & derivatives*
Estriol / metabolism
Gene Expression Profiling / methods
Humans
Mice, Inbred C57BL
Neurons / metabolism*
RNA Splicing Factors
RNA, Messenger / metabolism*
RNA-Binding Proteins / genetics*

Substances

RBFOX1 protein, human
RNA Splicing Factors
RNA, Messenger
RNA-Binding Proteins
Rbfox1 protein, mouse
estriol succinate
Estriol

Abstract

Publication types

MeSH terms

Substances

Grants and funding