Journal Article

<i>RBFOX1</i> regulates both splicing and transcriptional networks in human neuronal development

Brent L. Fogel, Eric Wexler, Amanda Wahnich, Tara Friedrich, Chandran Vijayendran, Fuying Gao, Neelroop Parikshak, Genevieve Konopka and Daniel H. Geschwind

in Human Molecular Genetics

Volume 21, issue 19, pages 4171-4186
Published in print October 2012 | ISSN: 0964-6906
Published online June 2012 | e-ISSN: 1460-2083 | DOI:
RBFOX1 regulates both splicing and transcriptional networks in human neuronal development

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RNA splicing plays a critical role in the programming of neuronal differentiation and, consequently, normal human neurodevelopment, and its disruption may underlie neurodevelopmental and neuropsychiatric disorders. The RNA-binding protein, fox-1 homolog (RBFOX1; also termed A2BP1 or FOX1), is a neuron-specific splicing factor predicted to regulate neuronal splicing networks clinically implicated in neurodevelopmental disease, including autism spectrum disorder (ASD), but only a few targets have been experimentally identified. We used RNA sequencing to identify the RBFOX1 splicing network at a genome-wide level in primary human neural stem cells during differentiation. We observe that RBFOX1 regulates a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins. Downstream alterations in gene expression define an additional transcriptional network regulated by RBFOX1 involved in neurodevelopmental pathways remarkably parallel to those affected by splicing. Several of these differentially expressed genes are further implicated in ASD and related neurodevelopmental diseases. Weighted gene co-expression network analysis demonstrates a high degree of connectivity among these disease-related genes, highlighting RBFOX1 as a key factor coordinating the regulation of both neurodevelopmentally important alternative splicing events and clinically relevant neuronal transcriptional programs in the development of human neurons.

Journal Article.  10071 words.  Illustrated.

Subjects: Genetics and Genomics

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