The textbook description of the cilium is typically that of the motile, mucus-clearing cilia of the airway epithelia. There are a number of other systems in which motile cilia perform important functions, which I will discuss below, but in general 9+2 cilia such as those in the airways perform functions which utilize the cilia beat in order to allow cells and microorganisms to interact with fluids. Most commonly, these interactions
are used for motility of the entire cell or organism and to drive the transport of fluids. Ciliary motility is generated by the action of the molecular motor axonemal dynein. As I mentioned earlier, cytoplasmic dynein is one of the motors responsible for organelle transport along microtubules in the cell. In order to walk along a microtubule, dynein and other molecular motors typically have two globular heads which alternate binding to the microtubule in order to walk along it and convey the cargo attached to the tail of the motor. Microtubules are polar structures with ends typically termed plus and minus ends. Dynein and another molecular motor, kinesin, form two superfamilies of proteins of which the various types are found in various species. Dynein only moves toward the minus-end of the microtubule, while kinesin is a plus-end directed motor. In addition to transport within the cell, the cargo-carrying function performed by these motors also drives intraflagellar transport (IFT), the process which is responsible for the construction of the cilium as well as trafficking along the cilium (Satir and Christensen, 2007).
As opposed to when it is carrying cargo, to produce cilia bending axonemal dynein walks along one doublet microtubule, while the tail is fixed to an adjacent doublet mi- crotubule. Because the adjacent doublets are fixed at the base of the cilium this walking motion results in a bending deformation of the cilium. Approximately 3,000 dyneins per cilium generate the forces between doublet microtubules that produce bending, but in general the mechanisms by which the action of each dynein are coordinated into a stable, oscillatory motion of the cilium are not known.
Observations of dysfunctional cilia, as well as the example provided by the motile primary cilium in the embryonic node, suggest that the ‘natural’ beat of a cilium is helical or conical. In contrast, the more typical motile cilium typically beats with a back-and-forth, whiplike motion in what is often called a planar beat. Thus, it is ex- pected that the additional structural elements provided by the two singlet microtubules
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Figure 2
A schematic of a cross-section of a typical “9+2” eucaryotic axonemer. Reproduced from Cooper (2000).
flagellum is a rigid structure with a corkscrew shape and is rotated by a single motor (Berg 1975). In contrast, the eucaryotic flagellum has an elaborate internal structure, the axoneme, that is powered by dynein molecular motors distributed regularly along its length and circumference. Although the patterns of eucaryotic flagellar movement are distinct from those of ciliary movement, and flagella are typically much longer than cilia, their basic ultrastructure is identical. A schematic of a cross section of the typical “9+2” axoneme is shown inFigure 2. This cross section consists of a central pair of singlet microtubules surrounded by nine outer doublet microtubules and encased by the cell membrane (see Murase 1992, Witman 1990 for review). The nine outer doublets are connected by radial spokes to a sheath surrounding the central pair. In addition, the outer doublets are connected by protein structures, named nexin links, between adjacent pairs of doublets. The bending of the axoneme is caused by sliding between pairs of outer doublets. Active sliding is due to the unidirectional ATP-induced force generation of the dynein power stroke. Backward, passive sliding is due to the active sliding of other pairs of doublets within the axoneme. The radial spokes and central tubule couples are involved in the regulation of activity necessary in producing effective motion (Omoto 1991). The precise nature of the spatial and temporal control mechanisms regulating the various flagellar and ciliary beats is still unknown (Brokaw 2001).
Considerable interest has focused on understanding how the local force production of the dynein motors is translated into the controlled, regular beating of the global structure. An accurate mechanical model should include an explicit representation of the force generation and activation dynamics of the dynein molecular motors, and the forces due to the passive structure of the microtubules, nexin links, and radial arms. These forces should be coupled to the viscous hydrodynamics of the surrounding fluid.
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Figure 3.4: From Fauci et al. (2006). The ultrastructure of a 9+2 cilium. The doublet
microtubules around the perimeter are connected by the inner and outer dynein arms. Dynein generates forces between the doublets which generate cilia bending. The direction of the planar beat of most motile cilia is the direction perpendicular to the line which joins the centers of the singlet microtubules in the core of the axoneme.
in 9+2 cilia are responsible for this beat type. Structurally, these singlet microtubules are coupled to the ring of doublet microtubules by radial spokes, and there are also nexin links between adjacent doublets as depicted in Figure3.4(Satir and Christensen,
2007; Hirokawa, 1998).
The planar beat shape of the airway cilium is the most well-studied. Although over one beat cycle the cilium stays roughly within a single plane, the beat itself can be deconstructed into an ‘effective stroke’, which is typically in the direction that the cilia drives fluid flow, and a ‘recovery stroke’ which is opposite the direction of fluid flow (Satir and Christensen, 2007). These two parts of the beat cycle are differentiated by changes in the contour of the cilium. During the effective stroke the cilium is essentially straight, while in the recovery stroke the cilium bends to a larger degree such that its tip is at a lower height than during the effective stroke. This shape change is critical to the success of this type of cilium in driving fluid transport at low Reynolds number, because without inertia a simple change in velocity with no associated shape change will not produce transport.