Understanding the importance of cilia as Wnt-signaling organelles

In processes ranging from larval development to respiration, mucociliary membranes defend epithelia against irritants and pathogens by a directional mucous flow generated through the coordinated beating of motile cilia. Deficiency of these nanopropellers leads to airway disease and ciliopathies, and understanding their cell biology is important for the rational design of cilio-stimulatory therapies. Hence, understanding their cell biology is important for the rational design of cilio-stimulatory therapies.

Cilia and Wnt signaling have a complex relationship, wherein Wnt regulates cilia and, conversely, cilia may affect Wnt signaling. Recently, we showed that Wnt receptors are present in flagella, primary cilia, and multicilia, where they transmit an intraciliary signal that is independent of β-catenin. Intraciliary Wnt signaling promotes ciliogenesis, affecting male fertility, adipogenesis, and mucociliary clearance. Wnt also stimulates the beating of motile cilia, highlighting that these nanomotors too, are chemosensory. Intraciliary Wnt signaling employs a Wnt- protein phosphatase 1 (PP1) signaling axis, involving the canonical Wnt pathway's inhibition of GSK3 to repress PP1 activity. Collectively, these findings support that cilia are Wnt signaling organelles, with implications for ciliopathies and cancer.

Our working hypothesis is that Wnt ┫PP1 signaling is physiologically relevant in other mammalian ciliated cells and tissues. To answer in which physiological processes and tissues does primary and mucociliary Wnt signaling play a role in e.g. mouse, we need to deconvolute the requirement for Wnt signaling in the plethora of other tissues and processes wherein the pathway is involved from those where specifically ciliary Wnt signaling is involved. Towards this end we are studying mouse mutants in which components specific for ciliary Wnt signaling are inactivated.

1. Zhang K, Da Silva F, Seidl C, Wilsch-Bräuninger M, Herbst J, Huttner WB, Niehrs C. (2023) Primary cilia are WNT-transducing organelles whose biogenesis is controlled by a WNT-PP1 axis. Dev Cell 58:139-154.
2. Seidl C, Da Silva F, Zhang K, Wohlgemuth K, Omran H, Niehrs C. (2023) Mucociliary Wnt signaling promotes cilia biogenesis and beating. Nat Commun. 6; 14:1259.
3. Niehrs C, Da Silva F, Seidl C. (2024) Cilia as Wnt signaling organelles. Trends Cell Biol. doi: 10.1016/j.tcb.2024.04.001