Deficiency of CPEB2-Confined Choline Acetyltransferase Expression in the Dorsal Motor Nucleus of Vagus Causes Hyperactivated Parasympathetic Signaling-Associated Bronchoconstriction.
Cytoplasmic polyadenylation element binding protein 2 (CPEB2) is an RNA-binding protein and translational regulator. To understand the physiological function of CPEB2, we generated CPEB2 knock-out (KO) mice and found that most died within 3 d after birth. CPEB2 is highly expressed in the brainstem, which controls vital functions, such as breathing. Whole-body plethysmography revealed that KO neonates had aberrant respiration with frequent apnea. Nevertheless, the morphology and function of the respiratory rhythm generator and diaphragm neuromuscular junctions appeared normal. We found that upregulated translation of choline acetyltransferase in the CPEB2 KO dorsal motor nucleus of vagus resulted in hyperactivation of parasympathetic signaling-induced bronchoconstriction, as evidenced by increased pulmonary acetylcholine and phosphorylated myosin light chain 2 in bronchial smooth muscles. Specific deletion of CPEB2 in cholinergic neurons sufficiently caused increased apnea in neonatal pups and airway hyper-reactivity in adult mice. Moreover, inhalation of an anticholinergic bronchodilator reduced apnea episodes in global and cholinergic CPEB2-KO mice. Together, the elevated airway constriction induced by cholinergic transmission in KO neonates may account for the respiratory defect and mortality.



This study first generated and characterized cpeb2 gene-deficient mice. CPEB2-knock-out (KO) mice are born alive but most die within 3 d after birth showing no overt defects in anatomy. We found that the KO neonates showed severe apnea and altered respiratory pattern. Such respiratory defects could be recapitulated in mice with pan-neuron-specific or cholinergic neuron-specific ablation of the cpeb2 gene. Further investigation revealed that cholinergic transmission in the KO dorsal motor nucleus of vagus was overactivated because KO mice lack CPEB2-suppressed translation of the rate-limiting enzyme in the production of acetylcholine (i.e., choline acetyltransferase). Consequently, increased parasympathetic signaling leads to hyperactivated bronchoconstriction and abnormal respiration in the KO neonates.
Institute of Biomedical Sciences, Academia Sinica, 11529 Taipei, Taiwan.|Graduate Institute of Microbiology, College of Medicine, National Taiwan University, 10051 Taipei, Taiwan, and.
Yen-Ting
0000-0002-8627-3231
YT
Lai
Institute of Biomedical Sciences, Academia Sinica, 11529 Taipei, Taiwan.
Chun-Kuei
CK
Su
National Laboratory Animal Center, National Applied Research Laboratories, 10622 Tainan, Taiwan.
Si-Tse
ST
Jiang
Institute of Biomedical Sciences, Academia Sinica, 11529 Taipei, Taiwan.
Ya-Jen
YJ
Chang
Institute of Biomedical Sciences, Academia Sinica, 11529 Taipei, Taiwan.
Alan Chuan-Ying
AC
Lai
Institute of Biomedical Sciences, Academia Sinica, 11529 Taipei, Taiwan, yishuian@ibms.sinica.edu.tw.
Yi-Shuian
0000-0001-9000-7748
YS
Huang
D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology*; D001993:Bronchodilator Agents / Q000494:pharmacology; D002795:Choline O-Acetyltransferase / Q000096:biosynthesis*; D003964:Diaphragm / Q000294:innervation / Q000502:physiology; D005260:Female; D005838:Genotype; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000502:physiology; D009469:Neuromuscular Junction / Q000502:physiology; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000235:genetics*; D015656:Respiratory Mechanics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation; D014630:Vagus Nerve / Q000187:drug effects / Q000201:enzymology*
D001993:Bronchodilator Agents; C483243:CPEB2 protein, mouse; D016601:RNA-Binding Proteins; D002795:Choline O-Acetyltransferase
CPEB; ChAT; DMNV; SIDS; bronchoconstriction; translational control