NOVA regulates Dcc alternative splicing during neuronal migration and axon guidance in the spinal cord

• DOI: 10.7554/elife.14264
• Publication Date: 2016-05-25T12:01:14Z
• Authors: Janelle C Leggere; Yuhki Saito; Robert B Darnell; Marc Tessier-Lavigne; Harald J Junge; Zhe Chen
• Keywords: 0301 basic medicine; NOVA; QH301-705.5; Knockout; Science; Commissural Interneurons; alternative splicing; Mice; 03 medical and health sciences; Antigens, Neoplasm; Neuro-Oncological Ventral Antigen; Animals; Developmental; Genetic Testing; Antigens; Biology (General); DCC; Mice, Knockout; neuronal migration; axon guidance; Q; R; Gene Expression Regulation, Developmental; RNA-Binding Proteins; DCC Receptor; Axon Guidance; 3. Good health; Alternative Splicing; Developmental Biology and Stem Cells; Gene Expression Regulation; Spinal Cord; Neoplasm; Medicine; RNA Interference; RNA binding proteins

RNA-binding proteins (RBPs) control multiple aspects of post-transcriptional gene regulation and function during various biological processes in the nervous system. To further reveal the functional significance of RBPs during neural development, we carried out an in vivo RNAi screen in the dorsal spinal cord interneurons, including the commissural neurons. We found that the NOVA family of RBPs play a key role in neuronal migration, axon outgrowth, and axon guidance. Interestingly, Nova mutants display similar defects as the knockout of the Dcc transmembrane receptor. We show here that Nova deficiency disrupts the alternative splicing of Dcc, and that restoring Dcc splicing in Nova knockouts is able to rescue the defects. Together, our results demonstrate that the production of DCC splice variants controlled by NOVA has a crucial function during many stages of commissural neuron development.