Abstract
Motile cilia/flagella are essential for swimming and generating extracellular fluid flow in eukaryotes. Motile cilia harbor a 9+2 arrangement consisting of nine doublet microtubules with dynein arms at the periphery and a pair of singlet microtubules at the center (central pair). In the central system, the radial spoke has a T-shaped architecture and regulates the motility and motion pattern of cilia. Recent cryoelectron tomography data reveal three types of radial spokes (RS1, RS2, and RS3) in the 96 nm axoneme repeat unit; however, the molecular composition of the third radial spoke, RS3 is unknown. In human pathology, it is well known mutation of the radial spoke head-related genes causes primary ciliary dyskinesia (PCD) including respiratory defect and infertility. Here, we describe the role of the primary ciliary dyskinesia protein Rsph4a in the mouse motile cilia. Cryoelectron tomography reveals that the mouse trachea cilia harbor three types of radial spoke as with the other vertebrates and that all triplet spoke heads are lacking in the trachea cilia of Rsph4a-deficient mice. Furthermore, observation of ciliary movement and immunofluorescence analysis indicates that Rsph4a contributes to the generation of the planar beating of motile cilia by building the distal architecture of radial spokes in the trachea, the ependymal tissues, and the oviduct. Although detailed mechanism of RSs assembly remains unknown, our results suggest Rsph4a is a generic component of radial spoke heads, and could explain the severe phenotype of human PCD patients with RSPH4A mutation.
Highlights
Primary ciliary dyskinesia (PCD) is a recessive genetic disease caused by defects in motile cilia function
radial spokes (RSs) consists of the spoke head and the stalk, and the three-types of RS (RS1, RS2, RS3) exist in the axoneme of motile cilia
The Rsph4a KO mice show hydrocephalus which is a typical phenotype of PCD (Fig 1A)
Summary
Primary ciliary dyskinesia (PCD) is a recessive genetic disease caused by defects in motile cilia function. The mouse multiple motile cilia have a 9+2 type geometry that contains nine peripheral doublet microtubules with dynein arms, single microtubules at the center of the axoneme (central pair; CP), and radial spokes (RSs). The proportion of respiratory cilia with normal axonemal structure is 50% in human RSPH4A patients [18], whereas it is 80% in RSPH1 patients [16], suggesting that the phenotype of the RSPH4A mutation is more severe than the RSPH1 mutation. Another RSs-related protein, RSPH3 is critical for the assembly of radial spoke in the human respiratory cilia and its mutation causes PCD [21]. Rsph6a is essential for the assembly of mouse sperm flagella and fertility [22]
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