Characterization of a new brain-specific isoform of the EWS oncoprotein

EWS and related TAFII68 and TLS/FUS genes are fused with different genes en coding transcription factors in various human cancers. The products of thes e genes have the ability to bind RNA and have been shown to be part of spli cing and transcription complexes. We show that the EWS, TAFII68 and TLS/FUS proteins are expressed to various levels in all adult murine tissues. We c haracterize a new isoform of EWS that is specifically expressed in the cent ral nervous system, in both mice and humans. It is shown to be related to a splice variant which includes a new 18-bp exon, termed 4', between exon 4 and 5. The detection of this isoform in spontaneously differentiating SH-SY 5Y neuroblastoma cells and in nerve growth factor-induced PC12 cells furthe r links this isoform to neural differentiation. RT-PCR experiments indicate that the level of expression of the brain-specific EWS isoform is stable d uring brain development whereas that of the ubiquitous EWS isoform decrease s during this period. The two isoforms show a parallel decrease in expressi on after birth. The 4' exon is not detected in tumour-specific EWS fusion t ranscripts, suggesting that its presence may impair their oncogenic propert ies. Interestingly, sequences of the 4' exon and flanking regions show rema rkable similarities to that of the neural-specific c-src exon, suggesting c ommon mechanisms for the alternative splicing of these exons. The phylogene tic conservation and relationship to neural differentiation strongly sugges ts an important functional role for this exon.