NOVA2-mediated RNA regulation is required for axonal pathfinding during development

eLife - Tập 5
Yuhki Saito1, Soledad Miranda‐Rottmann1, Matteo Ruggiu1, Christopher Y. Park2, John J. Fak1, Zhong Ru1, Jeremy S. Duncan3, Brian A. Fabella4, Harald J. Junge5, Zhe Chen5, Roberto Araya6, Bernd Fritzsch3, A. J. Hudspeth4, Robert B. Darnell7,2
1Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
2New York Genome Center, New York, United States
3Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, United States
4Laboratory of Sensory Neuroscience, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
5Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Boulder, United States
6Department of Neurosciences, Faculty of Medicine, University of Montreal, Montreal, Canada
7Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States; New York Genome Center, New York, United States

Tóm tắt

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.

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