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ScienceWeek
CELL BIOLOGY: ON THE FORMATION OF CILIA
The following points are made by O. Bossinger and A. Bachmann (Current Biology 2004 14:R844):
1) Virtually all eukaryotic cilia and flagella are remarkably similar in their organization, with a central bundle of microtubules called the axoneme in which nine outer doublet microtubules surround a central pair of single microtubules (the 9+2 scheme). These microtubules are enclosed by a membrane that is contiguous with the cell membrane. While the mammalian spermatozoon and the unicellular green alga Chlamydomonas have only one or two flagella, respectively, the unicellular protozoan Paramecium carries a few thousand cilia on its surface. Most mammalian cells, however, carry on their surface a non-motile primary cilium which lacks the central pair of single microtubules (the 9+0 scheme).Cilia contribute to locomotion, fluid movement, chemoreception, and patterning of the left-right body axis. Defects in their formation and function are associated with polycystic kidney disease, retinal degeneration and the inherited left-right inversion known as "situs inversus" (e.g., the liver developing on the left side rather than on the right side.)
2) Cilia are assembled and maintained by a process called intraflagellar transport (IFT), which was first studied in the biflagellate alga Chlamydomonas reinhardtii but which is also now receiving increasing attention in other model organisms [1]. IFT is generally believed to involve transport of cargo needed for assembly, maintenance, and function of cilia and flagella. A basic question in cell biology today addresses the mechanisms underlying this process.(2)
3) Two protein complexes, Crb3-Pals1-Patj and Par3-Par6-aPKC, have been shown to be involved in the establishment of intercellular junctions along the lateral membrane domain [3]. These junctions have a number of functions: they connect epithelial cells and separate their membrane domains; they are involved in the regulation of paracellular transport; and they create a diffusion barrier between different biological compartments. In vertebrates, the latter functions are provided by the tight junction. Components of the tight junction are conserved in invertebrates, where they localize to the subapical region/marginal zone [4].
4) The Crb3-Pals1-Patj complex contains the transmembrane protein Crb3, which recruits the MAGUK protein Pals1 and the multi-PDZ domain protein Patj. The Par3-Par6-aPKC complex includes the three-PDZ-domain-containing protein Par3, the single PDZ domain protein Par6, and an atypical protein kinase C. Both protein complexes are interconnected by interactions of Par6 with either Pals1 or Crb3 [5]. The large number of protein-protein interaction domains provided by these protein scaffolds is thought to recruit additional signaling molecules and may also provide a link to the cytoskeleton in epithelial cells.
References (abridged):
1. Rosenbaum, J.L. and Witman, G.B. (2002). Intraflagellar transport. Nat. Rev. Mol. Cell Biol. 3, 813-825
2. Fan, S., Hurd, T.W., Liu, C., Straight, S.W., Weimbs, T., Hurd, E.A., Domino, S.E. and Margolis, B. (2004). Polarity proteins control ciliogenesis via kinesin motor interactions. Curr. Biol. 14, 1451-1461
3. Nelson, W.J. (2003). Adaptation of core mechanisms to generate cell polarity. Nature 422, 766-774
4. Knust, E. and Bossinger, O. (2002). Composition and formation of intercellular junctions in epithelial cells. Science 298, 1955-1959
5. Hurd, T.W., Gao, L., Roh, M.H., Macara, I.G. and Margolis, B. (2003). Direct interaction of two polarity complexes implicated in epithelial tight junction assembly. Nat. Cell Biol. 5, 137-142
Current Biology http://www.current-biology.com
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Related Material:
LEFT-RIGHT DEVELOPMENT: CONSERVED FUNCTION FOR EMBRYONIC NODAL CILIA.
The following points are made by J.J. Essner et al (Nature 2002 418:37):
1) How left-right handedness originates in the body plan of the developing vertebrate embryo is a subject of considerable debate. In mice, a left-right bias is thought to arise from a directional extracellular flow (nodal flow) that is generated by dynein-dependent rotation of monocilia on the ventral surface of the embryonic node.
2) The authors report that the existence of node monocilia and the expression of a dynein gene that is implicated in ciliary function are conserved across a wide range of vertebrate classes, indicating that a similar ciliary mechanism may underlie the establishment of handedness in all vertebrates.
3) In mice, mutations in the gene that encodes the left-right dynein heavy chain (Lrd), a component of the ciliary motor, result in immotile node cilia and a reversal of the left-right (L-R) axis in roughly half of mutant offspring.
4) In humans, mutations in the dynein heavy-chain gene DNAH5 are also associated with immotile cilia syndrome, an inherited disorder that includes mirror-image reversal of the internal organs in half of affected individuals. Both Lrd and Dnahc5 are expressed in the ventral layer of the mouse node in cells containing cilia.
Nature http://www.nature.com/nature
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Related Material:
CELL BIOLOGY: A PHYSICAL ANALYSIS OF CILIARY BEATING
Notes by ScienceWeek:
The structural framework ("cytoskeleton") of eukaryotic cells (cells with nuclei and other membrane-bound internal structures) consists of an arrangement of macromolecular structures: microtubules, intermediate filaments, and microfilaments. The microtubules are hollow cylinders about 24 nanometers in diameter, many microns in length, and consist of heterodimers of alpha- and beta-tubulin proteins plus a variable set of other proteins. They form the scaffolding of the mitotic spindle (an important structure in cell division), organize other cytoplasmic structures, and are the structural core of various organelles involved in cell movement (cilia and flagella).
Cilia and flagella are motile membrane-enclosed appendages that project from the surface of certain types of cells. Depending on the cell type involved, these motile appendages perform one of two alternative functions: 1) cells that are firmly anchored in place use ciliary motion to move fluids across their surfaces; and 2) cells that are not anchored, such as sperm cells or unicellular organisms, use the movement of cilia or flagella to propel themselves through the fluid medium in which they are suspended.
Although cilia and flagella are closely related structures, they can be distinguished from each other on the basis of differences in size, number, and pattern of movement. Cilia are much shorter than flagella, usually approximately 5 to 10 microns in length, more numerous on any particular cell surface, and move in a complex patter whose net result is to propel fluid across the cell surface.
In this context, the term "metachronal rhythm" refers to a pattern of ciliary movement (ciliary beating) in which each cilium is at a slightly different stage in the beat cycle from those on either side of it, the result a smooth progression of waves of beating along the units.
At the molecular level, the present consensus is that ciliary movement is produced by microtubules sliding past one another (rather than by microtubules contracting), and that this microtubule sliding is in turn produced by the motor protein dynein, which has been identified as comprising specific protrusions in the form of "dynein arms" in the internal structure of the cilium. The transient attachments and movements of various dynein arms in a single cilium are evidently highly coordinated to produce precise bending and movement of the cilium.
At the present time, delineation of the detailed internal structure of cilia and the role of dynein arms in ciliary movement are the focus of research in a number of laboratories.
The following points are made by S. Gueron and K. Levit-Gurevich (Proc. Natl. Acad. Sci. 1099 96:12240):
1) The internal mechanism of cilia is among the most ancient biological motors on an evolutionary scale, producing beat patterns that consist of 2 phases: a) during the effective stroke, the cilium moves approximately as a straight rod, and b) during the recovery stroke, the cilium rolls close to the surface in a tangential motion. It is commonly agreed that these 2 phases produce efficient functioning: the effective stroke encounters strong viscous resistance and generates thrust, whereas the recovery stroke returns the cilium to the starting position while avoiding viscous resistance.
2) Metachronal coordination between cilia, which occurs when many cilia beat close to each other, is believed to be an autonomous result of the hydrodynamical interactions of the system. Qualitatively, metachronism is perceived as a mechanism for reducing the energy expenditure required for beating.
3) The authors developed a method for computing the work done by model cilia that beat in a viscous fluid. The theoretical framework used by the authors consists of 3 building blocks linked together: a) a hydrodynamic description of the ciliary system; b) geometric equations for the motion of the cilia; c) a model internal bend-generating mechanism.
4) The authors report that for a single cilium beating in water, the mechanical work done during the effective stroke is approximately 5 times the amount of work done during the recovery stroke. Investigation of multicilia configurations indicates that having neighboring cilia beat metachronally is energetically advantageous and "perhaps even crucial for multiciliary functioning." Finally, the authors report the use of the model to approximate the number of dynein arm attachments that are likely to occur during the effective and recovery strokes of a beat cycle, the model predicting that almost all of the available dynein arms should participate in generating the motion.
Proc. Nat. Acad. Sci. http://www.pnas.org
ScienceWeek http://scienceweek.com
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