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 knockout (KO) mice and found that most died within 3 days after birth. CPEB2 is highly expressed in the brainstem, which controls vital functions like breathing. Whole-body plethysmography revealed that KO neonates had aberrant respiration with frequent apnea. Nevertheless, the morphology and function of respiratory rhythm generator and diaphragm neuromuscular junctions appeared normal. We found that upregulated translation of choline acetyltransferase (ChAT) in the CPEB2 KO dorsal motor nucleus of vagus (DMNV) 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 hyperreactivity in adult mice. Moreover, inhalation of an anticholinergic bronchodilator reduced apnea episodes in global and cholinergic CPEB2-KO mice. Taken 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 KO mice are born alive but most die within 3 days 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- or cholinergic neuron-specific ablation of cpeb2 gene. Further investigation revealed that cholinergic transmission in the KO DMNV was overactivated because of lacking CPEB2-suppressed translation of the rate-limiting enzyme in the production of acetylcholine (i.e. ChAT). Consequently, increased parasympathetic signaling leads to hyperactivated bronchoconstriction and abnormal respiration in the KO neonates.Journal Link 期刊連結