Bench To Bedside: New Findings in Primary Ciliary Dyskinesia

By Joseph H. Sisson, MD; and Johnny L. Carson, PhD

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Background

With minor variations, the ultrastructural organization of eukaryotic cilia and flagella is uniform across the phylogenetic spectrum and the protein components comprising the axoneme exhibit wide conservation. Ciliary beds are present in the epithelium lining the human respiratory airways, the vestibular epithelium of the brain, and the fallopian tubes, and flagella are present as organelles of locomotion in human sperm (Fig 1).

Cilia, when viewed in cross-section by electron microscopy, are approximately 300 nm in diameter. The internal structure of the cilium is highly organized and optimal function of the organelle is clearly mandated by organization of these components in the correct spatial orientation. Cross-sections of cilia reveal a radially symmetric pattern of nine peripheral microtubular pairs surrounding a central microtubular pair (Fig 2). One of the microtubules of each peripheral microtubular pair exhibits an inner and an outer dynein arm. Several other accessory structures, such as radial spokes and interdoublet links, also are evident in the cross-sectioned cilium. When viewed in longitudinal section, microtubules can be seen extending continuously along almost the entire length of the ciliary shaft. A longitudinal view of the axoneme provides an even more salient view of the dynein arms, particularly in freeze-fracture preparations. Here, both dynein arms are positioned at discrete intervals along the microtubular pairs.^2,3 The ciliary membrane also exhibits a specialized feature, best viewed in freeze-fracture preparations: the ciliary necklace, which appears as an array of membrane-associated particles at the base of each cilium. Although clearly related to effecting ciliary function, this structure has not been rigorously dissected at the molecular level. Both ciliary and flagellar activities are directed by the same basic mechanism, a molecular motor driven by the sliding interaction of axonemal microtubules and dynein adenosinetriphosphatases (ATPases). In order to accomplish the effective and return ciliary/flagellar stroke, the microtubular components of the axoneme undergo a sliding motility relative to one another. This sliding action is effected by a cycle of attachment, sliding, and release of dynein ATPases located on adjacent peripheral microtubular pairs. Accessory axonemal structures are thought to provide shear resistance that converts this sliding action to the bending/beating action of the intact axoneme.

In isolated experimental preparations of axonemes devoid of the native accessory structures present in the whole cilium, the microtubular pairs can be seen to slide away from their neighbors in the presence of adenosine triphosphate.^4-6 It is thought that the presence of the various accessory axonemal structures, such as radial spokes and interdoublet links, provide structural shear resistance to convert microtubular sliding to bending in the intact axoneme, thus conferring ciliary beat. Although present elsewhere in the cell and almost universally in eukaryotic cells, microtubules contribute prominently to the cytoskeletal architecture of cilia and flagella. Microtubules are assembled into a tubular helix from homodimers of a- and b-tubulin protofilaments, each with a molecular weight of approximately 55,000 d.⁷ There is evidence of posttranslational modification of axonemal a-tubulin by acetylation in Chlamydomonas, suggesting a fundamental difference between cytoplasmic and axonemal a-tubulin.^8,9 Similarly, dynein ATPases exhibit cilia and ciliated-cell specificity. Dynein heavy chains can be segregated into cytoplasmic and axonemal forms. There are one to three heavy chains in a functional dynein as well as a variable number of intermediate and light chains.¹⁰ Dynein heavy chains occur as cytoplasmic, inner axonemal arm, and outer axonemal arm forms.^11-13 Illustrative of the conserved nature of dynein heavy chain genes is the greater similarity of the homologs of a given chain across species than to other dynein heavy chains within the same species.

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