Alternative splicing by NOVA factors: From gene expression to cell physiology and pathology

Abstract

NOVA1 and NOVA2, the two members of the NOVA family of alternative splicing factors, bind YCAY clusters of pre-mRNAs and assemble spliceosomes to induce the maintenance/removal of introns and exons, thus governing the development of mRNAs. Members of other splicing families operate analogously. Activity of NOVAs accounts for up to 700 alternative splicing events per cell, taking place both in the nucleus (co-transcription of mRNAs) and in the cytoplasm. Brain neurons express high levels of NOVAs, with NOVA1 predominant in cerebellum and spinal cord, NOVA2 in the cortex. Among brain physiological processes NOVAs play critical roles in axon pathfinding and spreading, structure and function of synapses, as well as the regulation of surface receptors and voltage-gated channels. In pathology, NOVAs contribute to neurodegenerative diseases and epilepsy. In vessel endothelial cells, NOVA2 is essential for angiogenesis, while in adipocytes, NOVA1 contributes to regulation of thermogenesis and obesity. In many cancers NOVA1 and also NOVA2, by interacting with specific miRNAs and by additional mechanisms, activate oncogenic roles promoting cell proliferation, colony formation, migration, and invasion. In conclusion, NOVAs regulate cell functions of physiological and pathological nature. Single cell identification and distinction, and new therapies addressed to NOVA targets might be developed in the near future.