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.
Highlights
During central nervous system (CNS) development, a neuron extends its axon through a complex yet precise path to reach its final destination by sensing extracellular signals called guidance cues
We provide evidence for a novel and unique role for the tissue specific splicing regulator NOVA2 as an axon pathfinding modifier in cortical CC axons, motoneuron, and auditory efferents
Integration of transcriptome-wide HITS-crosslinking and immunoprecipitation (CLIP) analysis, exon junction microarray data sets, and bioinformatics led to the identification of a large set of NOVA1/2 RNA functional interaction sites and major biological pathways which NOVA1/2 orchestrates in vivo
Summary
During central nervous system (CNS) development, a neuron extends its axon through a complex yet precise path to reach its final destination by sensing extracellular signals called guidance cues. These cues are sensed by the growth cone, a motile structure at the extending axon edge, and they control growth cone motility through directed cytoskeletal remodeling. The spinal cord commissural axon reaching the midline senses netrin-1, secreted from the floorplate as a chemoattractive cue; once it has crossed the floorplate, this cue becomes repulsive
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