shorter primary cilia in the kidney (7, 11). It was suggested that these cilia function in the kidney to sense ionic concentrations, disturbance of which leads to disease. Similar mutants lacking kinesin-II motor or raft complex homologues in Caenorhabditis elegans disturb the structure and function of nonmotile chemosensory cilia (6).
Perhaps the most distinctive use of nonmotile cilia is presented by the vertebrate photoreceptor. This neuronal cell has an axon, but in place of a typical dendritic arbor it has a cellular compartment called the inner segment in which most biosynthesis takes place. Components such as opsin that are needed to sense light then are transported to sites of utilization in the disks of the outer segment (Fig. 1). Transport appears to occur through a narrow isthmus or connecting cilium, which is structurally a typical nonmotile cilium. A substantial amount of material must be moved through the connecting cilium because the photoreceptor turns over ca. 10% of its mass daily. Thus, it is perhaps not surprising that kinesin-II has been reported by a number of groups to be localized in the connecting cilium of the photoreceptor (14–16). These observations suggested that the transport system found in more typical cilia and flagella might be harnessed to move opsin, and perhaps other photoreceptor components, from the inner segment to the outer segment through the connecting cilium. Recently, specific removal of kinesin-II from photoreceptors using the lox-cre system was found to cause a substantial accumulation of opsin and arrestin in the inner segment accompanied by apoptosis. It was suggested that this phenotype was caused by a defect in transport of opsin and arrestin from the inner segment to the outer segment (17). Similar phenotypes have been seen in a particular class of opsin mutants that cause retinitis pigmentosa in humans. These mutants have been suggested to interfere with opsin transport and cause opsin accumulation in the inner segment and apoptosis (18–20). The region of opsin to which these mutants map also appears to interact with the dynein molecular motor (21), further suggesting a role for transport dysfunction in the development of degenerative retinal diseases such as retinitis pigmentosa. As with primary ciliary dyskinesia, it is tempting to speculate that
the collection of genes encoding the components required for transport from the inner segment to the outer segment, and in particular for opsin transport, may represent susceptibility loci for retinitis pigmentosa and other diseases where photoreceptor degeneration is a central feature. Indeed, it is intriguing that myosin VIIA, which when mutant can cause retinitis pigmentosa in humans (but curiously not mice), has been suggested to play a minor role in opsin transport and to be localized in the connecting cilium of the photoreceptor in addition to the retinal pigment epithelium (22, 23).
Finally, in thinking about neuronal transport pathways, it is striking that kinesin-II has been found in many typical neurons that lack cilia (24–27). In Drosophila, mutants lacking a kinesin-II subunit exhibit defects in axonal transport of choline acetyltransferase, a possibly cytosolic enzyme (28). In mammals, antibody inhibition, two-hybrid and biochemical experiments suggest a direct functional linkage between kinesin-II and non-erythroid spectrin (fodrin) in neurons (29). Perhaps nonciliated neurons also use a raft-based kinesin-II transport system to move cytoplasmic proteins in association with membrane-associated rafts or vesicles. An intriguing possibility is that kinesin-II and associated raft complexes might play an important role in the movement of cytosolic proteins by the slow axonal transport system. Further experimental work is needed to test this idea.
Conventional kinesin, kinesin-I, was first discovered in a squid fast axoplasmic transport system, prompting early suggestions that kinesin-I would be an important motor protein to power fast anterograde axonal transport. This suggestion has been amply supported by a large number of antibody, antisense, and genetic experiments that support a general role of kinesin-I in axonal transport, but have not clearly linked this motor protein to a particular type of vesicular cargo (reviewed in ref. 30). It is thus not surprising that a “receptor” that mediates the attachment of kinesin-I to vesicular cargoes and other organelles has been elusive. In addition, whether it is the kinesin heavy chain (KHC) or the kinesin light chain (KLC) subunit of kinesin-I (Fig. 2) that binds to cargo has been unclear. Although a protein called kinectin has been suggested to play a role in linking kinesin-I to vesicles in non-neuronal cells (31, 32), its apparent absence in mammalian axons, Drosophila, and Caenorhabditis (33–35) has motivated additional searches for kinesin-I cargo receptors. Two serious candidates recently have emerged. One called Sunday driver was found in a genetic screen for axonal transport mutants in Drosophila (36). The other called amyloid precursor protein (APP) was identified initially in biochemical experiments (37).
The genetic screen that identified syd was based on work in Drosophila that revealed a constellation of phenotypes common to mutants defective in components of the anterograde or