Flagellar assembly occurs at the distal tip of the organelle, which is far from the site of protein synthesis in the cell body. As a result, intraflagellar transport (IFT) is required to transport flagellar precursors to their assembly site. Because mature flagella continuously undergo protein turnover, IFT is also required for flagellar maintenance.
The movement of IFT particles to the tip of the flagellum is powered by kinesin-II, a microtubule-based molecular motor. The movement of IFT particles back to the base of the flagellum is driven by cytoplasmic dynein 1b (also known as cytoplasmic dynein 2), another microtubule-based molecular motor.
IFT particles in the model organism Chlamydomonas are composed of at least 16 different polypeptides, virtually all of which have homologues in other ciliated organisms, including Caenorhabditis elegans and mammals.
Defects in either the IFT-motor or -particle proteins prevent normal ciliary assembly. As a result, genetic disruption or modification of genes that encode IFT proteins have led to important new insights into the functions of some types of cilia that had previously received scant attention.
Reduced expression of an IFT-particle protein in the mouse impairs assembly of the non-motile primary cilia in the kidney, which leads to polycystic kidney disease. Further studies have shown that the polycystins — proteins that are implicated in most cases of polycystic kidney disease in humans — are located on the primary cilia. These results have led to the hypothesis that the kidney primary cilium is a sensory organelle that is involved in the control of cell differentiation and proliferation.
Disruption of IFT-motor and -particle protein subunits prevents normal development and maintenance of the mouse photoreceptor outer segment. This is due to impaired transport through the connecting cilium, which is the only link between the inner segment, where protein synthesis occurs, and the outer segment. The result is slow degeneration of the retina, similar to that seen in some diseases that cause blindness in humans.
Knockout of IFT-motor subunits in the mouse prevents the assembly of nodal cilia in the embryo, which leads to situs inversus — a condition in which left–right asymmetry is abnormal. Further studies have shown that the movement of nodal cilia causes a directional fluid flow, which is proposed to set up a morphogenetic gradient that establishes correct left–right patterning during early development.
IFT is essential for the formation and maintenance of all cilia and flagella, so defects in IFT probably affect several organ systems — including the kidney and eye — in humans. Therefore, defects in IFT might underlie human syndromes such as Senior–Loken syndrome, Jeune syndrome and Bardet–Biedl syndrome, which are characterized by both cystic kidneys and retinal degeneration.
IFT might also have a direct role in the control of flagellar length by regulating the rate at which flagellar precursors are delivered to the tip of the flagellum.
Eukaryotic cilia and flagella, including primary cilia and sensory cilia, are highly conserved organelles that project from the surfaces of many cells. The assembly and maintenance of these nearly ubiquitous structures are dependent on a transport system — known as 'intraflagellar transport' (IFT) — which moves non-membrane-bound particles from the cell body out to the tip of the cilium or flagellum, and then returns them to the cell body. Recent results indicate that defects in IFT might be a primary cause of some human diseases.
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This work was supported by National Institutes of Health grants (J.L.R. and G.B.W.), and by The Robert W. Booth Fund at the Greater Worcester Community Foundation (G.B.W.).
- NODAL CILIA
(Also called monocilia). The primary cilia that are located on the ventral surface of the node of the early mammalian embryo. They are unusual among primary cilia in that they are motile. This motility generates a directional fluid flow across the node, which initiates signalling events that lead to the normal development of left–right asymmetry in the organism.
- SITUS INVERSUS
A condition in which internal body organs are in an inverse position relative to normal.
- PLUS OR MINUS END
Microtubules are polar structures that grow more rapidly by the addition of new subunits to one end (the 'plus' end) than to the other end (the 'minus' end). The minus ends of flagellar outer doublet microtubules are continuous with the microtubules of the basal body, and their plus ends are at the distal tip of the flagellum.
Pigmented cells, present in fish and other vertebrates, in which pigment granules rapidly disperse or aggregate by moving along the microtubules that radiate from the centre of the cells. This causes the skin to darken or lighten, respectively. The movement of granules is controlled by neurostimulation, and aggregation is driven by cytoplasmic dynein, whereas dispersion depends on a member of the kinesin superfamily.
- TRANSITION FIBRES
The fibres that emanate from the distal end of each of the triplet microtubules that comprise the flagellar basal body, and that attach the basal body to the cell membrane at the point where the cell membrane becomes the flagellar membrane.
A graphical description for the structure of a Ca2+-binding motif that was first described in parvalbumin.
Unicellular eukaryotic organisms, including algae and protozoans.
- SOMATOSTATIN RECEPTOR 3
One of at least five distinct G-protein-coupled receptors that bind somatostatin in mammals.
A protein subunit of microtubules.
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Rosenbaum, J., Witman, G. Intraflagellar transport. Nat Rev Mol Cell Biol 3, 813–825 (2002). https://doi.org/10.1038/nrm952
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