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Mucociliary Wnt signaling promotes cilia biogenesis and beating.

ABSTRACT: It is widely thought that Wnt/Lrp6 signaling proceeds through the cytoplasm and that motile cilia are signaling-inert nanomotors. Contrasting both views, we here show in the mucociliary epidermis of X. tropicalis embryos that motile cilia transduce a ciliary Wnt signal that is distinct from canonical β-catenin signaling. Instead, it engages a Wnt-Gsk3-Ppp1r11-Pp1 signaling axis. Mucociliary Wnt signaling is essential for ciliogenesis and it engages Lrp6 co-receptors that localize to cilia via a VxP ciliary targeting sequence. Live-cell imaging using a ciliary Gsk3 biosensor reveals an immediate response of motile cilia to Wnt ligand. Wnt treatment stimulates ciliary beating in X. tropicalis embryos and primary human airway mucociliary epithelia. Moreover, Wnt treatment improves ciliary function in X. tropicalis ciliopathy models of male infertility and primary ciliary dyskinesia (ccdc108, gas2l2). We conclude that X. tropicalis motile cilia are Wnt signaling organelles that transduce a distinct Wnt-Pp1 response.

SUBMITTER: Seidl C

PROVIDER: S-EPMC9988884 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Mucociliary Wnt signaling promotes cilia biogenesis and beating.

Seidl Carina C Da Silva Fabio F Zhang Kaiqing K Wohlgemuth Kai K Omran Heymut H Niehrs Christof C

Nature communications 20230306 1

It is widely thought that Wnt/Lrp6 signaling proceeds through the cytoplasm and that motile cilia are signaling-inert nanomotors. Contrasting both views, we here show in the mucociliary epidermis of X. tropicalis embryos that motile cilia transduce a ciliary Wnt signal that is distinct from canonical β-catenin signaling. Instead, it engages a Wnt-Gsk3-Ppp1r11-Pp1 signaling axis. Mucociliary Wnt signaling is essential for ciliogenesis and it engages Lrp6 co-receptors that localize to cilia via a ...[more]

PMID: 36878953

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Project description:BackgroundInspired air is heated and humidified in the nose before it reaches lower airways. This mechanism is bypassed during tracheostomy, directly exposing the airways to colder and drier air from the environment, known to negatively affect mucociliary transport; however, little is known about how quickly mucociliary transport deteriorates. This study determines the short-term effect of flowing room air and nebulized hypertonic saline and mannitol on mucociliary transport in the trachea. In an ovine perfused in vitro tracheal model (N = 9) the epithelium was exposed to 25 L/min of flow, heated to lamb body temperature (38 °C) and fully saturated with water vapor as the control, followed by either room air (22 °C and 50% relative humidity) or nebulized solutions of NaCl 7% and mannitol 20% up to 1 min for a short duration, until mucociliary transport had visually changed. Mucus transport velocity (MTV) and cilia beat frequency (CBF) were continuously measured with video-microscopy.ResultsExposing the tracheal epithelium to air heated to body temperature and fully humidified had stable MTV 9.5 ± 1.1 mm/min and CBF 13.4 ± 0.6 Hz. When exposed to flow of room air, MTV slowed down to 0.1 ± 0.1 mm/min in 2.0 ± 0.4 s followed by a decrease in CBF to 6.7 ± 1.9 Hz, after 2.3 ± 0.8 s. Both MTV and CBF recovered to their initial state when heated and humidified air-flow was re-introduced. Exposing the tracheal epithelium to nebulized hypertonic saline and nebulized mannitol for 1 min increased MTV without a subsequent increase in CBF.ConclusionsThis study demonstrates mucociliary transport can deteriorate within seconds of exposing the tracheal epithelium to flowing room air and increase rapidly when exposed to nebulized hypertonic solutions. The reduction in MTV precedes slowing of CBF with room air and MTV increases without a subsequent increase in CBF during the nebulization. Their relationship is non-linear and a minimum CBF of approximately 6 Hz is required for MTV > 0, while MTV can reach 10.9 mm/min without CBF increasing. Clinically these findings indicate a potential rapid detrimental effect of breathing with non-humidified air via bypassed upper airways and the short-term effects of nebulized osmotic agents that increase MTV.

Dataset Information

Mucociliary Wnt signaling promotes cilia biogenesis and beating.

Publications

Mucociliary Wnt signaling promotes cilia biogenesis and beating.

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