Genetic Evidence for a Nova Regulator of Alternative Splicing in the Brain

of neurons. This suggests that in addition to the general and Jasvinder Atwal splicing machinery, which is found ubiquitously (small Brain Tumor Research Centre nuclear ribonucleoprotein particles, RNA binding pro-Montreal Neurological Institute teins, and related factors), there must be specialized Montreal, Quebec, H3A 2B4 molecular machineries to direct regulation in a corre-Canada sponding cell type–specific manner. What are these specialized machineries, how do they recognize their Selected Reading specific intron targets, and how do they promote neu-ron-specific splicing? In the brain as well as in other function as splicing regulators for specific sets of alternatively spliced pre-mRNAs. It has been most provocative to note that Nova proteins are found exclusively in neuronal cells of the brain where they are localized to the cell nucleus—hence the prediction that these proteins might be tissue-specific regulators of alternative splicing. perform in the nucleus, and how important are these molecules for the survival and/or development of neu-rons? The study of Jensen et al. (2000) sheds new light on these questions by generating Nova-1 knockout mice. The Nova-1 null mice appear normal at birth, but How do genetic programs direct the development and die within about 2 weeks. The hallmark pathological physiology of distinct cell types in such complex sys-defect is neuronal cell death in precisely the regions of tems as brain, muscle, liver, and blood? In the brain, brainstem and spinal cord where Nova-1 is normally regulated alternative splicing is a major mechanism by expressed. Thus, Nova-1 is important for neuronal cell which neuronal cells acquire specialized molecular survival in the postnatal stage of development. structures and regulatory pathways needed to receive Is the physiological importance of Nova-1 due to it's and transmit informational signals. New biological func-role as a splicing regulator in brain? The Jensen et al. tions are generated by subtle alterations in protein (2000) study makes a strong case for this by demonstra-structure as a consequence of tissue-specific splicing ting significant splicing defects in the brains of Nova-1 patterns that occur in an impressive variety of morpho-null mice for neuron-specific exons of the inhibitory gly-logical patterns. In contrast to its biological utility, there cine receptor (GlyR␣2) and the ␥2 subunit of the GABA A is a dark side to tissue-specific splicing, since its misreg-receptor. There is no indication that general splicing is ulation is closely associated with some forms of malig-disrupted, but these particular neuron-specific splicing nant transformation, tumor metastasis, neurodegenera-events …