NPAS2
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Location (UCSC) | Chr 2: 100.82 – 101 Mb | Chr 1: 39.23 – 39.4 Mb | |||||||
PubMed search | [3] | [4] |
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Neuronal PAS domain protein 2 (NPAS2) also known as member of PAS protein 4 (MOP4) is a transcription factor protein that in humans is encoded by the NPAS2 gene.[5][6] NPAS2 is paralogous to CLOCK, and both are key proteins involved in the maintenance of circadian rhythms in mammals.[7] In the brain, NPAS2 functions as a generator and maintainer of mammalian circadian rhythms. More specifically, NPAS2 is an activator of transcription and translation of core clock and clock-controlled genes through its role in a negative feedback loop in the suprachiasmatic nucleus (SCN), the brain region responsible for the control of circadian rhythms.[8]
Discovery
The mammalian and mouse Npas2 gene was first sequenced and characterized in 1997 Dr. Steven McKnight's lab and published by Yu-Dong Zhou et al.[9][10] The gene’s cDNAs encoding mouse and human forms of NPAS2 were isolated and sequenced. RNA blotting assays were used to demonstrate the selective presence of the gene in brain and spinal cord tissues of mice. In situ hybridization indicated that the pattern of Npas2 mRNA distribution in mouse brain is broad and complex, and is largely non-overlapping with that of Npas1.[10]
Using
Structure
In humans
The Npas2 gene resides on chromosome 2 at the band q13.[10] The gene is 176,679 bases long and contains 25 exons.[11] The predicted 824-amino acid human NPAS2 protein shares 87% sequence identity with mouse Npas2.[10]
In mice
The Npas2 gene has been found to reside on chromosome 1 at 17.98 centimorgans and is 169,505 bases long.[12]
Function
In the brain
The NPAS2 protein is a member of the
Compensation is a key feature of TTFLs that regulate circadian rhythms. BMAL1 compensates for CLOCK in that if CLOCK is absent, BMAL1 will upregulate to maintain the mammalian circadian rhythms. NPAS2 has been shown to be analogous to the function of CLOCK in CLOCK-deficient mice.[8] In Clock knockout mice, NPAS2 is upregulated to keep the rhythms intact.[8] Npas2-mutant mice, which do not express functional NPAS2 protein, still maintain robust circadian rhythms in locomotion. However, like CLOCK-deficient mice in the CLOCK/BMAL1 TTFL, Npas2-mutant mice (in the NPAS2/BMAL1 TTFL) still have small defects in their circadian rhythms such as a shortened circadian period and an altered response to changes in the typical light-dark cycle.[8] In addition, Npas2 knockout mice show sleep disturbances and have decreased expression of mPer2 in their forebrains.[13] Mice without functional alleles of both Clock and Npas2 became arrhythmic once placed in constant darkness, suggesting that both genes have overlapping roles in maintaining circadian rhythms. In both wild-type and Clock knockout mice, Npas2 expression is observed at the same levels, confirming that Npas2 plays a role in maintaining these rhythms in the absence of Clock.[8]
In other tissues
Npas2 is expressed everywhere in the periphery of the body. Special focus has been given to its function in
Non-circadian function
NPAS2-deficient mice have been shown to have long-term memory deficits, suggesting that the protein may play a key role in the acquisition of such memories. This theory was tested by inserting a reporter gene (lacZ) that resulted in the production of an NPAS2 protein lacking the bHLH domain. These mice were then given several tests, including the cued and contextual fear task, and showed long-term memory deficits in both tasks.[14]
Interactions
NPAS2 has been shown to
- ARNTL (also known as BMAL1). Like Clock, Npas2 mRNA cycles with a similar phase to that of Bmal1, with both peaking 8 hours before the peak of Per2 mRNA expression. This is consistent with the observation that NPAS2 forms a heterodimer with BMAL1 to drive Per2 expression.[15][16]
- EP300. NPAS2 and EP300 interact in a time-dependent, synchronized manner. EP300 is recruited to NPAS2 as a coactivator of clock gene expression.[17]
- Retinoic acid receptor alpha (RARα) and retinoid X receptor alpha (RXRα). In peripheral clocks, RARα and RXRα interact with NPAS2 by inhibiting the NPAS2:BMAL1 heterodimer-mediated expression of clock genes. This interaction depends upon humoral signaling by retinoic acid and serves to phase-shift the clock.[15]
- Small heterodimer partner (SHP). In the liver circadian clock, NPAS2 and SHP engage in a TTFL: NPAS2 controls the circadian rhythms of SHP by rhythmically binding to its promoter, while SHP inhibits transcription of Npas2 when present.[18]
Clinical significance
Npas2 genotypes can be determined through tissue samples from which genomic DNA is extracted and assayed. The assay is performed under PCR conditions and can be used to determine specific mutations and polymorphisms.[19]
Polymorphisms and tumorigenesis
Mounting evidence suggests that the NPAS2 protein and other circadian genes are involved in
NPAS2 and mood disorders
Current research has revealed an association between
Associated with a connection to mood disorders, NPAS2 has been found to be involved with dopamine degradation. This was first suggested by the observation that the clock components BMAL1 and NPAS2 transcriptionally activated a
See also
- Clock (gene)
- Bmal1/Arntl (gene)
- Suprachiasmatic nucleus (SCN)
- Per (gene)
- Steven McKnight (scientist)
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000170485 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026077 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 9012850.
- S2CID 14908247.
- PMID 17417633.
- ^ PMID 19147932.
- PMID 9012850.
- ^ a b c d e "OMIM Entry: 603347 - Neuronal PAS Domain Protein 2 (NPAS2)". OMIM.
- ^ "NPAS2 neuronal PAS domain protein 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-04-20.
- ^ "Npas2 MGI Mouse Gene Detail - MGI:109232 - neuronal PAS domain protein 2". www.informatics.jax.org. Retrieved 2017-04-20.
- PMID 16996737.
- PMID 10864874.
- ^ S2CID 6251321.
- PMID 9576906.
- S2CID 11865543.
- S2CID 82270260.
- ^ PMID 19649706.
- PMID 28333141.
- S2CID 25985873.
- PMID 20072116.
- ^ S2CID 7006379.
- S2CID 36387074.
External links
- NPAS2+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Steven McKnight, the first scientist to implicate Npas2 as a contributor to circadian rhythms
This article incorporates text from the United States National Library of Medicine, which is in the public domain.