p75 neurotrophin receptor is a clock gene that regulates oscillatory components of circadian and metabolic networks
Open accessAbstract
The p75 neurotrophin receptor (p75(NTR)) is a member of the tumor necrosis factor receptor superfamily with a widespread pattern of expression in tissues such as the brain, liver, lung, and muscle. The mechanisms that regulate p75(NTR) transcription in the nervous system and its expression in other tissues remain largely unknown. Here we show that p75(NTR) is an oscillating gene regulated by the helix-loop-helix transcription factors CLOCK and BMAL1. The p75(NTR) promoter contains evolutionarily conserved noncanonical E-box enhancers. Deletion mutagenesis of the p75(NTR)-luciferase reporter identified the -1039 conserved E-box necessary for the regulation of p75(NTR) by CLOCK and BMAL1. Accordingly, gel-shift assays confirmed the binding of CLOCK and BMAL1 to the p75(NTR-)1039 E-box. Studies in mice revealed that p75(NTR) transcription oscillates during dark and light cycles not only in the suprachiasmatic nucleus (SCN), but also in peripheral tissues including the liver. Oscillation of p75(NTR) is disrupted in Clock-deficient and mutant mice, is E-box dependent, and is in phase with clock genes, such as Per1 and Per2. Intriguingly, p75(NTR) is required for circadian clock oscillation, since loss of p75(NTR) alters the circadian oscillation of clock genes in the SCN, liver, and fibroblasts. Consistent with this, Per2::Luc/p75(NTR-/-) liver explants showed reduced circadian oscillation amplitude compared with those of Per2::Luc/p75(NTR+/+). Moreover, deletion of p75(NTR) also alters the circadian oscillation of glucose and lipid homeostasis genes. Overall, our findings reveal that the transcriptional activation of p75(NTR) is under circadian regulation in the nervous system and peripheral tissues, and plays an important role in the maintenance of clock and metabolic gene oscillation.
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Loss of p75NTR alters the circadian oscillation of clock genes in the SCN, liver and fibroblasts, as well as glucose and lipid homeostasis genes.
“Loss of p75NTR alters the circadian oscillation of clock genes in the SCN, liver and fibroblasts, as well as glucose and lipid homeostasis genes [30].”
From Circadian control of glucose metabolism (2014) · cites this paper as [30]
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ARF Differentially Modulates Apoptosis Induced by E2F1 and Myc
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Circadian control of glucose metabolism
Kalsbeek, A., la Fleur, S., & Fliers, E. (2014) · Molecular Metabolism · doi:10.1016/j.molmet.2014.03.002 · Cited by 338 · see citing works
Circadian rhythms in glucose and lipid metabolism in nocturnal and diurnal mammals
Kumar Jha, P., Challet, E., & Kalsbeek, A. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2015.01.024 · Cited by 235 · see citing works
- Authors
- Baeza-Raja, B., Eckel-Mahan, K., Zhang, L., Vagena, E., Tsigelny, I. F., Sassone-Corsi, P., Ptacek, L. J., & Akassoglou, K.
- Affiliations
- Gladstone Institutes (US)
- San Diego Supercomputer Center (US)
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-06-19
- Volume
- 33
- Issue
- 25
- Pages
- 10221-10234
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3685830
- OpenAlex
- W2002625916
- Cited by
- 44
- References
- 103
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 6 · 2020: 5 · 2019: 2 · 2018: 7 · 2017: 4 · 2016: 2 · 2015: 3 · 2014: 2 · 2013: 1
- FWCI
- 1.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (P30-DK-63720, P30DK063720, P30DK026743)
- National Institute of Neurological Disorders and Stroke (NS051470, R01NS051470)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Molecular Biology Research
- Keywords
- p75 neurotrophin receptor, circadian clock, clock genes, clocks, Bmal1, helix-loop-helix transcription factors, transcriptional oscillations, suprachiasmatic nucleus, liver, glucose homeostasis, lipid homeostasis, Per1, Per2
- MeSH terms
- Animals, Blood Glucose, Circadian Rhythm, DNA, Homeostasis, Humans, Liver, Luciferases, Metabolism, Mice, Inbred C57BL, Motor Activity, Shock, Septic, Suprachiasmatic Nucleus, Transfection, Mice, Knockout, Receptor, Nerve Growth Factor, Electrophoretic Mobility Shift Assay, Mice, CLOCK Proteins, ARNTL Transcription Factors, HEK293 Cells, Real-Time Polymerase Chain Reaction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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