title: NPAS2 Compensates for Loss of CLOCK in Peripheral Circadian Oscillators.
abstract: Heterodimers of CLOCK and BMAL1 are the major transcriptional activators of the mammalian circadian clock. Because the paralog NPAS2 can substitute for CLOCK in the suprachiasmatic nucleus (SCN), the master circadian pacemaker, CLOCK-deficient mice maintain circadian rhythms in behavior and in tissues in vivo. However, when isolated from the SCN, CLOCK-deficient peripheral tissues are reportedly arrhythmic, suggesting a fundamental difference in circadian clock function between SCN and peripheral tissues. Surprisingly, however, using luminometry and single-cell bioluminescence imaging of PER2 expression, we now find that CLOCK-deficient dispersed SCN neurons and peripheral cells exhibit similarly stable, autonomous circadian rhythms in vitro. In CLOCK-deficient fibroblasts, knockdown of Npas2 leads to arrhythmicity, suggesting that NPAS2 can compensate for loss of CLOCK in peripheral cells as well as in SCN. Our data overturn the notion of an SCN-specific role for NPAS2 in the molecular circadian clock, and instead indicate that, at the cellular level, the core loops of SCN neuron and peripheral cell circadian clocks are fundamentally similar.
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego, California, United States of America.|Department of Psychiatry & Center for Circadian Biology, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Dominic
authors.initials: D
authors.lastname: Landgraf
authors.affiliation: Department of Psychiatry & Center for Circadian Biology, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Lexie L
authors.initials: LL
authors.lastname: Wang
authors.affiliation: Department of Psychiatry & Center for Circadian Biology, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Tanja
authors.initials: T
authors.lastname: Diemer
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego, California, United States of America.|Department of Psychiatry & Center for Circadian Biology, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: David K
authors.initials: DK
authors.lastname: Welsh
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D056926:CLOCK Proteins / Q000172:deficiency* / Q000378:metabolism; D057906:Circadian Clocks; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D015398:Signal Transduction; D013493:Suprachiasmatic Nucleus / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D009419:Nerve Tissue Proteins; C491259:Npas2 protein, mouse