Distinct N-methyl-D-aspartate receptor 2B subunit gene sequences confer neural and developmental specific expression.

Expression of the N-methyl--aspartate (NMDA) receptor 2B (NR2B) subunit is neural-specific and differentially regulated. It is expressed in the forebrain and in cerebellar granule cells at early postnatal stages and selectively repressed in the cerebellum after the second postnatal week, where it is replaced by the NR2C subunit. This switch confers distinct properties to the receptor. In order to understand the molecular mechanisms that differentially regulate the NR2B gene in the forebrain and cerebellum during development, we have isolated and characterized the promoter region of the NR2B gene. Two 5' noncoding exons and multiple transcription start sites were identified. Transcriptional analysis in transgenic mice reveals that an upstream 800-base pair region, which includes the first exon, is sufficient to direct neural-specific transcription. Developmental repression of the gene in the cerebellum requires additional regulatory elements residing in the first intron or second exon. Sequence elements that may participate in the regulation of the NR2B gene were identified by comparison to other neural genes. These studies provide insight into the molecular mechanisms regulating the switch of NMDA receptor subunit expression in the cerebellum, which ultimately account for the physiological changes in receptor function during development.