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2017 ; 8
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Developmental regulation of RNA processing by Rbfox proteins
#MMPMID27748060
Conboy JG
Wiley Interdiscip Rev RNA
2017[Mar]; 8
(2
): ä PMID27748060
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The Rbfox genes encode an ancient family of sequence-specific RNA binding
proteins (RBPs) that are critical developmental regulators in multiple tissues
including skeletal muscle, cardiac muscle, and brain. The hallmark of Rbfox
proteins is a single high-affinity RRM domain, highly conserved from insects to
humans, that binds preferentially to UGCAUG motifs at diverse regulatory sites in
pre-mRNA introns, mRNA 3'UTRs, and pre-miRNAs hairpin structures. Versatile
regulatory circuits operate on Rbfox pre-mRNA and mRNA to ensure proper
expression of Rbfox1 protein isoforms, which then act on the broader
transcriptome to regulate alternative splicing networks, mRNA stability and
translation, and microRNA processing. Complex Rbfox expression is encoded in
large genes encompassing multiple promoters and alternative splicing options that
govern spatiotemporal expression of structurally distinct and tissue-specific
protein isoforms with different classes of RNA targets. Nuclear Rbfox1 is a
candidate master regulator that binds intronic UGCAUG elements to impact splicing
efficiency of target alternative exons, many in transcripts for other splicing
regulators. Tissue-specificity of Rbfox-mediated alternative splicing is executed
by combinatorial regulation through the integrated activity of Rbfox proteins and
synergistic or antagonistic splicing factors. Studies in animal models show that
Rbfox1-related genes are critical for diverse developmental processes including
germ cell differentiation and memory in Drosophila, neuronal migration and
function in mouse brain, myoblast fusion and skeletal muscle function, and normal
heart function. Finally, genetic and biochemical evidence suggest that
aberrations in Rbfox-regulated circuitry are risk factors for multiple human
disorders, especially neurodevelopmental disorders including epilepsy and autism,
and cardiac hypertrophy. WIREs RNA 2017, 8:e1398. doi: 10.1002/wrna.1398 For
further resources related to this article, please visit the WIREs website.
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