NOVA2-mediated RNA regulation is required for axonal pathfinding during development
- Howard Hughes Medical Institute, The Rockefeller University, United States
- New York Genome Center, United States
- University of Iowa, United States
- University of Colorado, Boulder, United States
- University of Montreal, Canada
Abstract
The neuron specific RNA-binding proteins NOVA1 and NOVA2 are highly homologous alternative splicing regulators. NOVA proteins regulate at least 700 alternative splicing events in vivo, yet relatively little is known about the biologic consequences of NOVA action and in particular about functional differences between NOVA1 and NOVA2. Transcriptome-wide searches for isoform-specific functions, using NOVA1 and NOVA2 specific HITS-CLIP and RNA-seq data from mouse cortex lacking either NOVA isoform, reveals that NOVA2 uniquely regulates alternative splicing events of a series of axon guidance related genes during cortical development. Corresponding axonal pathfinding defects were specific to NOVA2 deficiency: Nova2-/- but not Nova1-/- mice had agenesis of the corpus callosum, and axonal outgrowth defects specific to ventral motoneuron axons and efferent innervation of the cochlea. Thus we have discovered that NOVA2 uniquely regulates alternative splicing of a coordinate set of transcripts encoding key components in cortical, brainstem and spinal axon guidance/outgrowth pathways during neural differentiation, with severe functional consequences in vivo.
Article and author information
Author details
Reviewing Editor
- Huda Y Zoghbi, Baylor College of Medicine, United States
Ethics
Animal experimentation: This studies were performed in compliance with protocols (#14678 and #07069) approved by the Institutional Animal Care and Use Committee (IACUC) of the Rockefeller University or with protocols (13-185 and 15-002) approved by the Comité de déontologie de l'expérimentation sur les animaux (CDEA) of the Univeristy of Montreal.
Version history
- Received: January 12, 2016
- Accepted: May 23, 2016
- Accepted Manuscript published: May 25, 2016 (version 1)
- Version of Record published: July 1, 2016 (version 2)
Copyright
© 2016, Saito et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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NOVA2-mediated RNA regulation is required for axonal pathfinding during development
eLife 5:e14371.
https://doi.org/10.7554/eLife.14371
Further reading
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- Cell Biology
- Neuroscience
Alternative RNA splicing is an essential and dynamic process in neuronal differentiation and synapse maturation, and dysregulation of this process has been associated with neurodegenerative diseases. Recent studies have revealed the importance of RNA-binding proteins in the regulation of neuronal splicing programs. However, the molecular mechanisms involved in the control of these splicing regulators are still unclear. Here, we show that KIS, a kinase upregulated in the developmental brain, imposes a genome-wide alteration in exon usage during neuronal differentiation in mice. KIS contains a protein-recognition domain common to spliceosomal components and phosphorylates PTBP2, counteracting the role of this splicing factor in exon exclusion. At the molecular level, phosphorylation of unstructured domains within PTBP2 causes its dissociation from two co-regulators, Matrin3 and hnRNPM, and hinders the RNA-binding capability of the complex. Furthermore, KIS and PTBP2 display strong and opposing functional interactions in synaptic spine emergence and maturation. Taken together, our data uncover a post-translational control of splicing regulators that link transcriptional and alternative exon usage programs in neuronal development.
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