Vagal regulation of respiratory clocks in mice.
The present study addresses the role of the circadian system in day-night changes of respiratory functions in the mouse. In all airway tissues investigated (i.e., larynx, trachea, bronchus, and lung), we observed clear rhythmic expression of the Per1, Per2, Bmal1, and Clock core oscillator genes (the latter two genes oscillating in antiphase with the Per genes), as well as the clock-regulated Dbp gene. Oscillations were abolished in arrhythmic Cry1-/- Cry2-/- knock-out mice and after lesioning of the master clock in the suprachiasmatic nucleus (SCN) in wild-type animals. These findings indicate that respiratory system cells contain a functional peripheral oscillator that is controlled by the SCN. Furthermore, we found that the muscarinic acetylcholine receptor genes Chm2, Chm3, and Chm4 are expressed in a circadian manner, and that mucin secretion (rather than synthesis) by the airway submucosal glands is under circadian control. Signals from the SCN are mainly transmitted by the vagal nerve because unilateral vagotomy completely abolished rhythms in mucin and PER2 protein levels in the (operated) ipsilateral side of the submucosal glands, but not in the (intact) contralateral side. Thus, peripheral clock mediated circadian expression of muscarinic acetylcholine receptor proteins, and parasympathetic signaling between SCN and respiratory tissues are essential gears in conferring circadian "time" information to airway glands.
Bando
Hideki
H
Division of Molecular Brain Science, Department of Brain Sciences, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
Nishio
Takeshi
T
van der Horst
Gijsbertus T J
GT
Masubuchi
Satoru
S
Hisa
Yasuo
Y
Okamura
Hitoshi
H
D056930:ARNTL Transcription Factors; D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology*; D007830:Larynx / Q000502:physiology; D008168:Lung / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009077:Mucins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D056950:Period Circadian Proteins; D011976:Receptors, Muscarinic / Q000378:metabolism; D012119:Respiration / Q000235:genetics*; D014132:Trachea / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014630:Vagus Nerve / Q000502:physiology*
D056930:ARNTL Transcription Factors; D000109:Acetylcholine; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D009077:Mucins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D011976:Receptors, Muscarinic; D015534:Trans-Activators; D014157:Transcription Factors; C431792:Arntl2 protein, mouse; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; C538944:Clock protein, mouse