The mechanisms of fast and slow transport in neurons: Identification and characterization of the new kinesin superfamily motors

Current Opinion in Neurobiology

Volumn 7, Issue 5, 1997, Pages 605-614

  Hirokawa, Nobutaka ^a  

^a UNIVERSITY OF TOKYO   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

KINESIN;

ADENOVIRUS; BIOPHYSICS; CARBOXY TERMINAL SEQUENCE; CELL ORGANELLE; GENE TECHNOLOGY; INTRACELLULAR TRANSPORT; NERVE CONDUCTION; NONHUMAN; PRIORITY JOURNAL; PROTEIN FAMILY; REVIEW; TRANSGENIC MOUSE; VIRUS RECOMBINANT;

EID: 0030727581     PISSN: 09594388     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-4388(97)80079-7     Document Type: Article

References (51)

1. Hirokawa N: Axonal transport and the cytoskeleton. Curr Opin Neurobiol 1993, 3:724-731.
2. Goldstein LSB: With apologies to Scheherazade: tails of 1001 kinesin motors. Annu Rev Genet 1993, 27:319-351.
3. Brady ST, Sperry AO: Biochemical and functional diversity of microtubule motors in the nervous system. Curr Opin Neurobiol 1995, 5:551-558.
4. Hirokawa N: Organelle transport along microtubules - the role of KIFs. Trends Cell Biol 1996, 6:135-141. This review introduces what is known about the new kinesin superfamily proteins (KIFs) - KIF1A, KIF1B, KIF2, KIF3A, KIF3B, KIF4, KIF5, uKHC, KIFC1, KIFC2 and KIFC3 - with regard to the mechanisms of organelle transport in cells and discusses how studying the different types of motors is helpful in the elucidation of the mechanism of mechanical force generation.
5. Takemura R, Nakata T, Okada Y, Yamazaki H, Zhang Z, Hirokawa N: mRNA expression of KIFA, KIF1B, KIF2, KIF3A, KIF3B, KIF4, KIF5, and cytoplasmic dynein during axonal regeneration. J Neurosci 1996, 16:31-35. To elucidate the role of individual kinesin superfamily motor proteins (KIFs) during the regenerative outgrowth of axons, this study examined the mRNA expression of KIF1A, KIF1B, KIF2, KIF3A, KIF3B, KIF4, KIF5, and cytoplasmic dynein 7-14 days after sciatic nerve crush. At these stages, the levels of KIF mRNAs examined were not increased, while the level of mRNA for cytoplasmic dynein was slightly increased, up to 140% of the original level. This result is consistent with the hypothesis that retrograde transport plays critical roles in regeneration, as is reflected by the transport of neurotrophic factors.
6. Aizawa H, Sekine Y, Takemura R, Zhang Z, Nangaku M, Hirokawa N: Kinesin superfamily in murine central nervous system. J Cell Biol 1992, 119:1287-1296.
7. Okada Y, Yamazaki H, Sekine-Aizawa Y, Hirokawa N: The neuron-specific kinesin superfamily protein KIF1A is a unique monomeric motor for anterograde axonal transport of synaptic vesicle precursors. Cell 1995, 81:769-780.
8. Nangaku M, Sato-Yoshitake R, Okada Y, Noda Y, Takemura R, Yamazaki H, Hirokawa N: KIF1B, a novel microtubule plus end-directed monomeric motor protein for mitochondria transport Cell 1994, 79:1209-1220.
9. Otsuka AJ, Jayaprakash A, Annoveros-Garcia J, Tang L, Fisk G, Hartshorne T, Franco R, Born T: The C. elegans unc-104 gene encodes a putative kinesin heavy chain-like protein. Neuron 1991, 6:113-122.
10. Li H-P, Liu Z-M, Nirenberg M: Kinesin-73 in the nervous system of Drosophila embryos. Proc Natl Acad Sci USA 1997, 94:1086-1099. This study identified a new Drosophila kinesin superfamily protein (KIF), kinesin-73, of the KIF1A/unc-104 subfamily. Although the motor domain is homologous to those of C. elegans unc-104 and mouse KIF1A, homology at the central region is low and at the carboxy-terminal region, kinesin-73 mRNA contains a cytoskeleton-associated protein glycine-rich domain. Kinesin-73 mRNA is maternally expressed and widely distributed in the syncytial blastoderm embryo. However, at later developmental stages, the kinesin-73 gene is expressed mostly in the nervous system.
11. Furlong RA, Zhou CY, Ferguson-Smith MA, Affara NA: Characterization of a kinesin-related gene ATSV, within the tuberous sclerosis locus (TSC1) candidate region on chromosome 9Q34. Genomics 1996, 33:421-429. This paper describes a cDNA with an open reading frame of 5070 basepairs that encodes a protein of 1690 amino acids. The putative protein product is a human homolog of the mouse kinesin superfamily protein KIF1A and is termed H-ATSV.
12. Noda Y, Sato-Yoshitake R, Kondo S, Nangaku M, Hirokawa N: KIF2 is a new microtubule-based anterograde motor that transports membranous organelles distinct from those carried by kinesin heavy chain or KIF3A/B. J Cell Biol 1995, 129:157-167.
13. Kondo S, Sato-Yoshitake R, Noda Y, Aizawa H, Nakata T, Matsuura Y, Hirokawa N: KIF3A is a new microtubule-based anterograde motor in the nerve axon. J Cell Biol 1994, 125:1095-1107.
14. Yamazaki H, Nakata T, Okada Y, Hirokawa N: KIF3A/3B: a heterotrimeric kinesin superfamily protein that works as a microtubule plus end-directed motor for membrane organelle transport. J Cell Biol 1995, 130:1387-1399.
15. Yamazaki H, Nakata T, Okada Y, Hirokawa N: Cloning and characterization of KAP3: a novel kinesin superfamily associated protein of KIF3A/3B. Proc Natl Acad Sci USA 1996, 93:8443-8448. In this study, kinesin superfamily protein (KIF) associated protein 3 (KAP3), which forms a heterotrimer complex with a KIF3A-KIF3B heterodimer, was purified. Full-length KAP3 cDNA from a mouse cDNA library was cloned and sequenced. Two isoforms of KAP3, KAP3A (793 amino acids) and KAP3B (772 amino acids), have been identified. Reconstitution studies in Sf9 cells indicated that KAP3 is a globular protein that binds to the tail domain of KIF3A/3B. Because KAP3 does not affect the ATPase activity of KIF3A/3B and because KAP3 binds to the tail region of KIF3A/3B, the authors suggested the possibility that KAP3 regulates the binding of the KIF3A/3B heterodimer to membranous organelles.
16. Cole DG, Cande WZ, Baskin RJ, Skoufias DA, Hogan CJ, Scholey JM: Isolation of a sea urchin egg kinesin-related protein using peptide antibodies. J Cell Sci 1992, 101:291-301.
17. (85/95). J Mol Biol 1995, 252:157-162.
18. Pesavento PA, Stewart RJ, Goldstein LSB: Characterization of the KLP68D kinesin-like protein of Drosophila: possible roles in axonal transport. J Cell Biol 1994, 127:1041-1048.
19. 85/95 heterodimer, thereby forming a heterotrimeric complex termed sea urchin kinesin II.
20. Sekine Y, Okada Y, Noda Y, Kondo S, Aizawa H, Takemura R, Hirokawa N: A novel microtubule-based motor protein (KIF4) for organelle transport whose expression is regulated developmentally. J Cell Biol 1994, 127:187-201.
21. Saito N, Okada Y, Yoda Y, Kinoshita Y, Kondo S, Hirokawa N: KIFC2 is a novel neuron-specific C-terminal-type kinesin super family M motor for dendritic transport of multivesicular body-like organelles. Neuron 1997, 18:425-438. The authors cloned the genes encoding two novel carboxy-terminal motor domain type kinesin superfamily motor proteins, KIFC1 and KIFC2, from mouse brain by utilizing a KIFC-specific consensus sequence. KIFC2 (792 amino acids) is a novel KIF that is specifically expressed in adult neurons. It was immunofluorescently localized to punctate structures in cell bodies and dendrites, but was not detected in axons. A quantitative immunoblotting study revealed that KIFC2 is present in peripheral nerve axons in very small amounts (0.1-0.3% of its levels in the cerebral cortex). Overexpression experiments indicated that KIFC2 is mainly localized to the cell body and dendrites in primary cultured hippocampal neurons. Together with immunoprecipitation data, this study showed that KIFC2 is a neuron-specific motor for the dendritic transport of multivesicular body like organelles.
22. Harlon DW, Yang Z, Goldstein LSB: Characterization of KIFC2, a neuronal kinesin superfamily member in mouse. Neuron 1997, 18:439-451. This paper describes the cDNA cloning and characterization of a new kinesin superfamily member, KIFC2, from mouse brain. Immunolocalization and biochemical fractionation suggest that KIFC2 localizes with some axonally transported organelles. On the basis of an immunofluorescence study of ligated peripheral nerves, the authors suggested that KIFC2 may play a role in retrograde axonal transport.
23. Nakagawa T, Tanaka Y, Matsuoka E, Kondo S, Okada Y, Noda Y, Kanai Y, Hirokawa N: Identification and classification of sixteen new kinesin superfamily (KIF) proteins in mouse genome. Proc Natl Acad Sci USA 1997, 94:9654-9659. This study identified 16 new kinesin superfamily proteins (KIFs) in mouse. The new KIFs were studied with respect to their expression patterns in different tissues and the chromosomal location of their genes. This study proposes a straightforward nomenclature system for the members of the mouse kinesin superfamily.
24. + channels.
25. Stenoien DL, Brady ST: Immunochemical analysis of kinesin light chain function. Mol Biol Cell 1997, 8:675-689. This study showed that a monoclonal antibody generated against a highly conserved epitope in the tandem repeat domain of kinesin light chains inhibited transport of membranous organelles by decreasing both the number and the velocity of moving vesicles. This antibody was equally effective at inhibiting both anterograde and retrograde transport and caused the release of kinesin from purified membrane vesicles. On the basis of these findings, the authors conclude that kinesin light chains play an important role in the interactions between kinesin and membranes.
26. Hirokawa N: Brain dynein localizes on both anterogradely and retrogradely transported membranous organelles in vivo. J Cell Biol 1990, 111:1027-1037.
27. Muresan V, Godek CP, Reese TS, Schnapp BJ: Plus-end motors override minus-end motors during transport of squid axon vesicles on microtubules. J Cell Biol 1996, 135:383-397. By analyzing the movements of vesicle populations that were bound to microtubule plus or minus ends in squid axoplasm, after various treatments, these authors reported that only plus-end-bound vesicles co-purified with tightly bound kinesin motors and that both plus- and minus-end-bound vesicles bound cytoplasmic dynein from cytosol. On the basis of these findings, the authors propose that the direction of vesicle movement could be regulated simply by the presence or absence of a tightly bound, plus-end-directed kinesin motor; being processive and tightly bound, the kinesin motor would override the activity of cytoplasmic dynein because the latter is weakly bound to vesicles and less processive.
28. Sato-Harada R, Okabe S, Umeyama T, Kanai Y, Hirokawa N: Microtubule-associated proteins regulate microtubule functions as the track for intracellular membrane organelle transports. Cell Struct Funct 1996, 21:283-295. This study, focusing on microtubule-associated proteins (MAPs), investigated the relationship between two functions of microtubules, as a track for organelle transport and a framework to maintain axonal morphology. Transfection of the tau or MAP2C gene into COS fibroblasts suppressed organelle movement almost completely. On the other hand, the application of dibutyryl cAMP, which phosphorylates endogenous tau protein in primary cultured sensory neurons and reduces the affinity of tau for microtubules, enhanced the transport of large organelles in the axon of primary cultured sensory neurons. Thus, these authors concluded that axonal MAPs can function as phosphorylation-dependent regulators of organelle transport.
29. Pfister KK, Salata MW, Dillman JF, Vaughan KT, Vallee RB, Torre E, Lye RJ: Differential expression and phosphorylation of the 74-kDa intermediate chains of cytoplasmic dynein in cultured neurons and glia. J Biol Chem 1996, 271:1687-1694. At least six different 74 kDa intermediate chains (IC74) of cytoplasmic dynein were found in extracts of dynein from brain. This study reports that cultured cortical neurons and glia express distinct IC74 isoforms. In glial cells, there is a single IC74 mRNA. Two isoforms of the protein, one the product of the single glial IC74 mRNA and the other its phospho-isoform, exist in glial cells.
30. Pfister KK, Salata MW, Dillman JF, Torre E, Lye RJ: Identification and developmental regulation of a neuron-specific subunit of cytoplasmic dynein. Mol Biol Cell 1996, 7:331-343. This study identified neuron-specific 74 kDa intermediate chain (IC74) subunits of cytoplasmic dynein. It also showed that the expression of IC74 isoforms is developmentally regulated in the brain, and the results indicate that the changes in neuronal IC74 isoforms coincide with neuronal differentiation, in particular with the extension of processes.
31. Dillman JF, Dabney LP, Pfister KK: Cytoplasmic dynein is associated with slow axonal transport. Proc Natl Acad Sci USA 1996, 93:141-144. This study, using radiolabeling and isolation of axonally transported proteins, showed that nearly 80% of anterogradely transported dynein was associated with slow transport, whereas only -15% was associated with the membranous organelles of anterograde fast axonal transport. The authors propose the hypothesis that cytoplasmic dynein generates the movement of microtubules in slow axonal transport.
32. Lasek RJ: Polymer sliding in axons. J Cell Biol 1986, 5(suppl):161-179.
33. Bamburg JB, Bray D, Chapman K: Assembly of microtubules at tips of growing axons. Nature 1986, 321:788-790.
34. Nixon RA: Slow axonal transport. Curr Opin Cell Biol 1992, 4:8-14.
35. Nixon RA, Logvinenko KB: Multiple fates of new synthesized neurofilament proteins: evidence for a stationary neurofilament network distributed nonuniformly along axons to retinal ganglion cell neurons. J Cell Biol 1986, 102:647-659.
36. Okabe S, Hirokawa N: Turnover of fluorescently labeled tubulin and actin in the axon. Nature 1990, 343:479-482.
37. Lim SS, Edson KJ, Letourneau PC, Borisy GG: A test of microtubule translocation during neurite elongation. J Cell Biol 1990, 111:123-130.
38. Okabe S, Hirokawa N: Dynamics of the neuronal intermediate filaments. J Cell Biol 1993, 121:375-396.
39. Takeda S, Okabe S, Funakoshi T, Hirokawa N: Differential dynamics of neurofilament-H protein and neurofilament-L protein in neurons. J Cell Biol 1994, 127:173-186.
40. Hirokawa N: The crosslinker system between neurofilaments, microtubules and membranous organelles in frog axons revealed by quick freeze, freeze fracture, deep etching method. J Cell Biol 1982, 94:129-142.
41. Reinsch SS, Mitchison TJ, Kirschner MW: Microtubule polymer assembly and transport during axonal elongation. J Cell Biol 1991, 115:365-379.
42. Okabe S, Hirokawa N: Differential behaviour of photoactivated microtubules in growing axons of mouse and frog neurons. J Cell Biol 1992, 117:105-120.
43. Okabe S, Hirokawa N: Do photobleached fluorescent microtubules move? Reevaluation of fluorescence laser photobleaching both in vitro and in growing Xenopus axons. J Cell Biol 1993, 120:1177-1186.
44. Sabry J, O'Connor TP, Kirschner MW: Axonal transport of tubulin in ti1 pioneer neurons in situ. Neuron 1995, 14:1247-1256.
45. Takeda S, Funakoshi T, Hirokawa N: Tubulin dynamics in neuronal axons of living zebrafish embryos. Neuron 1995, 14:1257-1264.
46. Funakoshi T, Takeda S, Hirokawa N: Active transport of photoactivated tubulin molecules in growing axons revealed by a new electron microscopic analysis. J Cell Biol 1996, 133:1347-1353. To investigate whether or not transported tubulin molecules are polymers, the authors made fluorescent marks on the tubulin molecules in the axons using a photoactivation technique and performed electron microscopic immunocytochemistry using anti-fluorescein antibody. Using this new method, high resolution and high sensitivity for detecting the transported tubulin molecules was achieved. In cells fixed after permeabilization, the authors found no translocated microtubules. In those fixed in the absence of permeabilization, in which cells oligomers and heterodimers in addition to polymers were preserved, the authors found a higher concentration of labeled tubulin in the regions distal to the photoactivated regions than in the proximal regions. These data indicated that tubulin molecules are transported not as polymers but as heterodimers or oligomers, by an active mechanism rather than by diffusion.
47. Ahmad FJ, Baas PW: Microtubules released from the neuronal centrosome are transported into the axon. J Cell Sci 1995, 108:2761-2769.
48. Miller KE, Joshi HC: Tubulin transport in neurons. J Cell Biol 1996, 133:1355-1366. This study was designed to re-examine a series of studies that showed that microtubules are recruited into the axons of neurons grown in the presence of a microtubule assembly inhibitor, vinblastine. The authors concluded that preformed microtubules moved into newly grown axons because vinblastine stabilizes bulk microtubule dynamics in vitro. By visualizing the polymerization of injected fluorescent tubulin, the authors showed that substantial microtubule polymerization occurs in neurons grown at the reported vinblastine concentrations. Importantly, the neuron growth condition of low vinblastine concentration allowed the authors to visualize the footprints of the tubulin wave as it polymerized and depolymerized during its slow axonal transport. In contrast, depolymerization-resistant fluorescent microtubules did not move when injected into neurons. This study showed that tubulin subunits, not microtubules, are the primary form of tubulin that is transported in axons.
49. Yu W, Schwei MJ, Baas PW: Microtubule transport and assembly during axon growth. J Cell Biol 1996, 133:151-157. To analyze the mechanism of the slow transport of tubulin, the authors micro-injected biotin-labeled tubulin into cultured neurons that had already grown short axons. The axons were then permitted to grow longer, after which the cells were prepared for immunoelectron microscopic analysis. In the newly grown region, the majority of the polymer was labeled while varying amounts of unlabeled polymer were also observed. From these results, the authors suggested that microtubule assembly and transport both contribute to the elaboration of the axonal microtubule array.
50. -1, more than four times the rate of axon elongation. Neither diffusion nor the en masse transport of axonal microtubules can account for the velocity and magnitude of tubulin transport that were observed. Thus, this study strongly suggested that most of the newly synthesized tubulin was supplied to the growing axon in the form of heterodimers or oligomers.
51. Terada S, Nakata T, Peterson AC, Hirokawa N: Visualization of slow axonal transport in vivo. Science 1996, 273:784-788. To answer important questions regarding the mechanism of slow transport of cytoskeletal proteins - namely, whether axonal neurofilaments are dynamic structures in which only subunits are transported or whether filaments assemble in the proximal axon and are transported intact as polymers to the axon terminus - the authors infected neurons of transgenic mice lacking axonal neurofilaments with a recombinant adenoviral vector encoding epitope-tagged neurofilament M (NF-M), which itself cannot form polymers. Confocal and electron microscopy revealed that the viral-encoded NF-M was transported in unpolymerized form along axonal microtubules. Thus, this study clearly indicated that neurofilament proteins are transported as subunits or small oligomers along microtubules, which are major routes for slow axonal transport.