TY - JOUR TI - NOVA2-mediated RNA regulation is required for axonal pathfinding during development AU - Saito, Yuhki AU - Miranda-Rottmann, Soledad AU - Ruggiu, Matteo AU - Park, Christopher Y AU - Fak, John J AU - Zhong, Ru AU - Duncan, Jeremy S AU - Fabella, Brian A AU - Junge, Harald J AU - Chen, Zhe AU - Araya, Roberto AU - Fritzsch, Bernd AU - Hudspeth, A J AU - Darnell, Robert B A2 - Zoghbi, Huda Y VL - 5 PY - 2016 DA - 2016/05/25 SP - e14371 C1 - eLife 2016;5:e14371 DO - 10.7554/eLife.14371 UR - https://doi.org/10.7554/eLife.14371 AB - 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. KW - HITS-CLIP KW - NOVA KW - splicing KW - axon guidance KW - RNA-seq KW - agenesis corpus callosum KW - motoneuron KW - cochlear neuron JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -