Neuron-specific splicing of zinc finger transcription factor REST/NRSF/XBRis frequent in neuroblastomas and conserved in human, mouse and rat

Neuron-restrictive silencer factor (NRSF), also known as repressor element REI binding transcription factor (REST) or repressor binding to the X2 box (XBR) (REST/NRSF/XBR), is a zinc finger transcription factor that during ea rly embryagenesis is required to repress a subset of neuron-specific genes in non-neural tissues and undifferentiated neural precursors. We have previ ously shown that splicing within the coding region of rat REST/NRSF/XBR (rR EST) generates several different transcripts all of which are expressed in the adult nervous system, rREST transcripts with short neuron-specific exon s (exon N) have in-frame stop codons and encode truncated proteins which ha ve an N-terminal repressor domain and weakened DNA binding activity. The ai m of this study was to analyze the regulatory mechanisms underlying REST/NR SF/XBR activity in human and mouse as compared to rat. We show that the str ucture of REST/NRSF/XBR gene and its regulation by neuron-specific splicing is conserved in human, mouse and mt. Expression levels of REST/NRSF/XBR tr anscripts with the insertion of exon N are increased during the neuronal di fferentiation of mouse teratocarcinoma PCC7 and rat pheocromocytoma PC12 ce lls and are high in several human and mouse neuroblastoma cells as compared to the relatively low levels in the developing and adult nervous system. T he exclusive expression of the neuronal forms of REST/NRSF/XBR mRNAs in mou se neuroblastoma Neuro-2A cells is not caused by rearrangement of the REST/ NRSF/XBR gene nor by mutations in the sequence of the splice sites flanking exon N. These data suggest that changes in REST/NRSF/XBR splicing pattern may result from altered levels of splicing factors reflecting the formation and/or progression of neuroblastoma tumors. (C) 1999 Elsevier Science B.V. All rights reserved.