p75 Neurotrophin Receptor Is a Clock Gene That Regulates Oscillatory Components of Circadian and Metabolic Networks

Abstract

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.