Dataset Information

Airway Ciliary Beating Affected by the Pcp4 Dose-Dependent [Ca²⁺]_i Increase in Down Syndrome Mice, Ts1Rhr.

ABSTRACT: In Ts1Rhr, a Down syndrome model mouse, the airway ciliary beatings are impaired; that is, decreases in ciliary beat frequency (CBF) and ciliary bend angle (CBA, an index of ciliary beat amplitude)). A resumption to two copies of the Pcp4 gene on the Ts1Rhr trisomic segment (Ts1Rhr:Pcp4^+/+/-) rescues the decreases in CBF and CBA that occur in Ts1Rhr. In airway cilia, upon stimulation with procaterol (a ?₂-agonist), the CBF increase is slower over the time course than the CBA increase because of cAMP degradation by Ca²⁺/calmodulin-dependent phosphodiesterase 1 (PDE1) existing in the metabolon regulating CBF. In Ts1Rhr, procaterol-stimulated CBF increase was much slower over the time course than in the wild-type mouse (Wt) or Ts1Rhr:Pcp4^+/+/-. However, in the presence of 8MmIBMX (8-methoxymethyl isobutylmethyl xanthine, an inhibitor of PDE1) or calmidazolium (an inhibitor of calmodulin), in both Wt and Ts1Rhr, procaterol stimulates CBF and CBA increases over a similar time course. Measurements of cAMP revealed that the cAMP contents were lower in Ts1Rhr than in Wt or in Ts1Rhr:Pcp4^+/+/-, suggesting the activation of PDE1A that is present in Ts1Rhr airway cilia. Measurements of the intracellular Ca²⁺ concentration ([Ca²⁺]_i) in airway ciliary cells revealed that temperature (increasing from 25 to 37 °C) or 4?PDD (a selective transient receptor potential vanilloid 4 (TRPV4) agonist) stimulates a larger [Ca²⁺]_i increase in Ts1Rhr than in Wt or Ts1Rhr:Pcp4^+/+/-. In airway ciliary cells of Ts1Rhr, Pcp4-dose dependent activation of TRPV4 appears to induce an increase in the basal [Ca²⁺]_i. In early embryonic day mice, a basal [Ca²⁺]_i increased by PCP4 expressed may affect axonemal regulatory complexes regulated by the Ca²⁺-signal in Ts1Rhr, leading to a decrease in the basal CBF and CBA of airway cilia.

SUBMITTER: Kogiso H

PROVIDER: S-EPMC7139761 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Airway Ciliary Beating Affected by the Pcp4 Dose-Dependent [Ca2+]i Increase in Down Syndrome Mice, Ts1Rhr.

Kogiso Haruka H Raveau Matthieu M Yamakawa Kazuhiro K Saito Daichi D Ikeuchi Yukiko Y Okazaki Tomonori T Asano Shinji S Inui Toshio T Marunaka Yoshinori Y Nakahari Takashi T

International journal of molecular sciences 20200312 6

In Ts1Rhr, a Down syndrome model mouse, the airway ciliary beatings are impaired; that is, decreases in ciliary beat frequency (CBF) and ciliary bend angle (CBA, an index of ciliary beat amplitude)). A resumption to two copies of the Pcp4 gene on the Ts1Rhr trisomic segment (Ts1Rhr:Pcp4+/+/-) rescues the decreases in CBF and CBA that occur in Ts1Rhr. In airway cilia, upon stimulation with procaterol (a β2-agonist), the CBF increase is slower over the time cour ...[more]

PMID: 32178446

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Project description:BackgroundPrimary ciliary dyskinesia (PCD) is a rare congenital respiratory disorder characterized by abnormal ciliary motility leading to chronic airway infections. Qualitative evaluation of ciliary beat pattern based on digital high-speed videomicroscopy analysis has been proposed in the diagnosis process of PCD. Although this evaluation is easy in typical cases, it becomes difficult when ciliary beating is partially maintained. We postulated that a quantitative analysis of beat pattern would improve PCD diagnosis. We compared quantitative parameters with the qualitative evaluation of ciliary beat pattern in patients in whom the diagnosis of PCD was confirmed or excluded.MethodsNasal nitric oxide measurement, nasal brushings and biopsies were performed prospectively in 34 patients with suspected PCD. In combination with qualitative analysis, 12 quantitative parameters of ciliary beat pattern were determined on high-speed videomicroscopy recordings of beating ciliated edges. The combination of ciliary ultrastructural abnormalities on transmission electron microscopy analysis with low nasal nitric oxide levels was the "gold standard" used to establish the diagnosis of PCD.ResultsThis "gold standard" excluded PCD in 15 patients (non-PCD patients), confirmed PCD in 10 patients (PCD patients) and was inconclusive in 9 patients. Among the 12 parameters, the distance traveled by the cilium tip weighted by the percentage of beating ciliated edges presented 96% sensitivity and 95% specificity. Qualitative evaluation and quantitative analysis were concordant in non-PCD patients. In 9/10 PCD patients, quantitative analysis was concordant with the "gold standard", while the qualitative evaluation was discordant with the "gold standard" in 3/10 cases. Among the patients with an inconclusive "gold standard", the use of quantitative parameters supported PCD diagnosis in 4/9 patients (confirmed by the identification of disease-causing mutations in one patient) and PCD exclusion in 2/9 patients.ConclusionsWhen the beat pattern is normal or virtually immotile, the qualitative evaluation is adequate to study ciliary beating in patients suspected for PCD. However, when cilia are still beating but with moderate alterations (more than 40% of patients suspected for PCD), quantitative analysis is required to precise the diagnosis and can be proposed to select patients eligible for TEM.

Dataset Information

Airway Ciliary Beating Affected by the Pcp4 Dose-Dependent [Ca²⁺]_i Increase in Down Syndrome Mice, Ts1Rhr.

Publications

Airway Ciliary Beating Affected by the <i>Pcp4</i> Dose-Dependent [Ca<sup>2+</sup>]<sub>i</sub> Increase in Down Syndrome Mice, Ts1Rhr.

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