NPAS2: An Analog of Clock Operative in the Mammalian Forebrain

Jul 7, 2001Science (New York, N.Y.)

NPAS2: a brain protein similar to the body’s internal clock in mammals

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Abstract

NPAS2 is associated with the transcription regulation of key circadian rhythm genes in mammalian forebrain cells.

Coinduction of NPAS2 and BMAL1 activates the transcription of Per1, Per2, and Cry1 genes.
These genes are involved in negatively regulating the circadian clock.
Transcription of the BMAL1 gene is repressed when NPAS2 and BMAL1 are coinduced.
In wild-type mice, Per1, Per2, and Cry1 mRNA levels rise during darkness and fall during light, while BMAL1 mRNA shows the opposite pattern.
In NPAS2-deficient mice, Per2 mRNA levels do not vary with the circadian cycle under constant darkness.

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Neuronal PAS domain protein 2 (NPAS2) is a transcription factor expressed primarily in the mammalian forebrain. NPAS2 is highly related in primary amino acid sequence to Clock, a transcription factor expressed in the suprachiasmatic nucleus that heterodimerizes with BMAL1 and regulates circadian rhythm. To investigate the biological role of NPAS2, we prepared a neuroblastoma cell line capable of conditional induction of the NPAS2:BMAL1 heterodimer and identified putative target genes by representational difference analysis, DNA microarrays, and Northern blotting. Coinduction of NPAS2 and BMAL1 activated transcription of the endogenous Per1, Per2, and Cry1 genes, which encode negatively activating components of the circadian regulatory apparatus, and repressed transcription of the endogenous BMAL1 gene. Analysis of the frontal cortex of wild-type mice kept in a 24-hour light-dark cycle revealed that Per1, Per2, and Cry1 mRNA levels were elevated during darkness and reduced during light, whereas BMAL1 mRNA displayed the opposite pattern. In situ hybridization assays of mice kept in constant darkness revealed that Per2 mRNA abundance did not oscillate as a function of the circadian cycle in NPAS2-deficient mice. Thus, NPAS2 likely functions as part of a molecular clock operative in the mammalian forebrain.

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NPAS2: An Analog of Clock Operative in the Mammalian Forebrain

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