G2Cdb::Gene report

Gene id
G00003245
Gene symbol
Kif5a (MGI)
Species
Mus musculus
Description
kinesin family member 5A
Orthologue
G00006235 (Homo sapiens)

Databases (3)

Gene
ENSMUSG00000074657 (Ensembl mouse gene)
16572 (Entrez Gene)
Marker Symbol
MGI:109564 (MGI)

Synonyms (4)

  • D10Bwg0738e
  • Khc
  • Kif5
  • Kns

Literature (36)

Pubmed - other

  • Stable kinesin and dynein assemblies drive the axonal transport of mammalian prion protein vesicles.

    Encalada SE, Szpankowski L, Xia CH and Goldstein LS

    Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, 92093, USA. sencalada@ucsd.edu

    Kinesin and dynein are opposite-polarity microtubule motors that drive the tightly regulated transport of a variety of cargoes. Both motors can bind to cargo, but their overall composition on axonal vesicles and whether this composition directly modulates transport activity are unknown. Here we characterize the intracellular transport and steady-state motor subunit composition of mammalian prion protein (PrP(C)) vesicles. We identify Kinesin-1 and cytoplasmic dynein as major PrP(C) vesicle motor complexes and show that their activities are tightly coupled. Regulation of normal retrograde transport by Kinesin-1 is independent of dynein-vesicle attachment and requires the vesicle association of a complete Kinesin-1 heavy and light chain holoenzyme. Furthermore, motor subunits remain stably associated with stationary as well as with moving vesicles. Our data suggest a coordination model wherein PrP(C) vesicles maintain a stable population of associated motors whose activity is modulated by regulatory factors instead of by structural changes to motor-cargo associations.

    Funded by: NIA NIH HHS: AG000216, AG032180, R01 AG032180, R01 AG032180-01, R01 AG032180-02, R01 AG032180-03, R01 AG032180-04, R01 AG032180-05, T32 AG000216; NIGMS NIH HHS: T32 GM008806; NINDS NIH HHS: P30 NS047101

    Cell 2011;144;4;551-65

  • A high-resolution anatomical atlas of the transcriptome in the mouse embryo.

    Diez-Roux G, Banfi S, Sultan M, Geffers L, Anand S, Rozado D, Magen A, Canidio E, Pagani M, Peluso I, Lin-Marq N, Koch M, Bilio M, Cantiello I, Verde R, De Masi C, Bianchi SA, Cicchini J, Perroud E, Mehmeti S, Dagand E, Schrinner S, Nürnberger A, Schmidt K, Metz K, Zwingmann C, Brieske N, Springer C, Hernandez AM, Herzog S, Grabbe F, Sieverding C, Fischer B, Schrader K, Brockmeyer M, Dettmer S, Helbig C, Alunni V, Battaini MA, Mura C, Henrichsen CN, Garcia-Lopez R, Echevarria D, Puelles E, Garcia-Calero E, Kruse S, Uhr M, Kauck C, Feng G, Milyaev N, Ong CK, Kumar L, Lam M, Semple CA, Gyenesei A, Mundlos S, Radelof U, Lehrach H, Sarmientos P, Reymond A, Davidson DR, Dollé P, Antonarakis SE, Yaspo ML, Martinez S, Baldock RA, Eichele G and Ballabio A

    Telethon Institute of Genetics and Medicine, Naples, Italy.

    Ascertaining when and where genes are expressed is of crucial importance to understanding or predicting the physiological role of genes and proteins and how they interact to form the complex networks that underlie organ development and function. It is, therefore, crucial to determine on a genome-wide level, the spatio-temporal gene expression profiles at cellular resolution. This information is provided by colorimetric RNA in situ hybridization that can elucidate expression of genes in their native context and does so at cellular resolution. We generated what is to our knowledge the first genome-wide transcriptome atlas by RNA in situ hybridization of an entire mammalian organism, the developing mouse at embryonic day 14.5. This digital transcriptome atlas, the Eurexpress atlas (http://www.eurexpress.org), consists of a searchable database of annotated images that can be interactively viewed. We generated anatomy-based expression profiles for over 18,000 coding genes and over 400 microRNAs. We identified 1,002 tissue-specific genes that are a source of novel tissue-specific markers for 37 different anatomical structures. The quality and the resolution of the data revealed novel molecular domains for several developing structures, such as the telencephalon, a novel organization for the hypothalamus, and insight on the Wnt network involved in renal epithelial differentiation during kidney development. The digital transcriptome atlas is a powerful resource to determine co-expression of genes, to identify cell populations and lineages, and to identify functional associations between genes relevant to development and disease.

    Funded by: Medical Research Council: MC_U127527203; Telethon: TGM11S03

    PLoS biology 2011;9;1;e1000582

  • Kinesin I transports tetramerized Kv3 channels through the axon initial segment via direct binding.

    Xu M, Gu Y, Barry J and Gu C

    Department of Neuroscience and Center for Molecular Neurobiology, The Ohio State University, Columbus, OH 43210, USA.

    Precise targeting of various voltage-gated ion channels to proper membrane domains is crucial for their distinct roles in neuronal excitability and synaptic transmission. How each channel protein is transported within the cytoplasm is poorly understood. Here, we report that KIF5/kinesin I transports Kv3.1 voltage-gated K(+) (Kv) channels through the axon initial segment (AIS) via direct binding. First, we have identified a novel interaction between Kv3.1 and KIF5, confirmed by immunoprecipitation from mouse brain lysates and by pull-down assays with exogenously expressed proteins. The interaction is mediated by a direct binding between the Kv3.1 N-terminal T1 domain and a conserved region in KIF5 tail domains, in which proper T1 tetramerization is crucial. Overexpression of this region of KIF5B markedly reduces axonal levels of Kv3.1bHA. In mature hippocampal neurons, endogenous Kv3.1b and KIF5 colocalize. Suppressing the endogenous KIF5B level by RNA interference significantly reduces the Kv3.1b axonal level. Furthermore, mutating the Zn(2+)-binding site within T1 markedly decreases channel axonal targeting and forward trafficking, likely through disrupting T1 tetramerization and hence eliminating the binding to KIF5 tail. The mutation also alters channel activity. Interestingly, coexpression of the YFP (yellow fluorescent protein)-tagged KIF5B assists dendritic Kv3.1a and even mutants with a faulty axonal targeting motif to penetrate the AIS. Finally, fluorescently tagged Kv3.1 channels colocalize and comove with KIF5B along axons revealed by two-color time-lapse imaging. Our findings suggest that the binding to KIF5 ensures properly assembled and functioning Kv3.1 channels to be transported into axons.

    Funded by: NINDS NIH HHS: R01 NS062720, R01 NS062720-01A1

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2010;30;47;15987-6001

  • A transposon in Comt generates mRNA variants and causes widespread expression and behavioral differences among mice.

    Li Z, Mulligan MK, Wang X, Miles MF, Lu L and Williams RW

    Department of Anatomy and Neurobiology, Center for Integrative and Translational Genomics, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.

    Background: Catechol-O-methyltransferase (COMT) is a key enzyme responsible for the degradation of dopamine and norepinephrine. COMT activity influences cognitive and emotional states in humans and aggression and drug responses in mice. This study identifies the key sequence variant that leads to differences in Comt mRNA and protein levels among mice, and that modulates synaptic function and pharmacological and behavioral traits.

    We examined Comt expression in multiple tissues in over 100 diverse strains and several genetic crosses. Differences in expression map back to Comt and are generated by a 230 nt insertion of a B2 short interspersed element (B2 SINE) in the proximal 3' UTR of Comt in C57BL/6J. This transposon introduces a premature polyadenylation signal and creates a short 3' UTR isoform. The B2 SINE is shared by a subset of strains, including C57BL/6J, A/J, BALB/cByJ, and AKR/J, but is absent in others, including DBA/2J, FVB/NJ, SJL/J, and wild subspecies. The short isoform is associated with increased protein expression in prefrontal cortex and hippocampus relative to the longer ancestral isoform. The Comt variant causes downstream differences in the expression of genes involved in synaptic function, and also modulates phenotypes such as dopamine D1 and D2 receptor binding and pharmacological responses to haloperidol.

    We have precisely defined the B2 SINE as the source of variation in Comt and demonstrated that a transposon in a 3' UTR can alter mRNA isoform use and modulate behavior. The recent fixation of the variant in a subset of strains may have contributed to the rapid divergence of inbred strains.

    Funded by: NIAAA NIH HHS: P20 AA017828, R01 AA013678, U01 AA013499, U01 AA013513, U01 AA014425, U01 AA016662, U01 AA016667, U01AA014425, U01AA016667, U01AA13499, U24AA13513; NIDA NIH HHS: P20 DA021131, P20-DA 21131

    PloS one 2010;5;8;e12181

  • An Oct4-centered protein interaction network in embryonic stem cells.

    van den Berg DL, Snoek T, Mullin NP, Yates A, Bezstarosti K, Demmers J, Chambers I and Poot RA

    Department of Cell Biology, Erasmus MC, Dr. Molewaterplein 50, Rotterdam, The Netherlands.

    Transcription factors, such as Oct4, are critical for establishing and maintaining pluripotent cell identity. Whereas the genomic locations of several pluripotency transcription factors have been reported, the spectrum of their interaction partners is underexplored. Here, we use an improved affinity protocol to purify Oct4-interacting proteins from mouse embryonic stem cells (ESCs). Subsequent purification of Oct4 partners Sall4, Tcfcp2l1, Dax1, and Esrrb resulted in an Oct4 interactome of 166 proteins, including transcription factors and chromatin-modifying complexes with documented roles in self-renewal, but also many factors not previously associated with the ESC network. We find that Esrrb associated with the basal transcription machinery and also detect interactions between transcription factors and components of the TGF-beta, Notch, and Wnt signaling pathways. Acute depletion of Oct4 reduced binding of Tcfcp2l1, Dax1, and Esrrb to several target genes. In conclusion, our purification protocol allowed us to bring greater definition to the circuitry controlling pluripotent cell identity.

    Funded by: Medical Research Council; Wellcome Trust

    Cell stem cell 2010;6;4;369-81

  • mNUDC is required for plus-end-directed transport of cytoplasmic dynein and dynactins by kinesin-1.

    Yamada M, Toba S, Takitoh T, Yoshida Y, Mori D, Nakamura T, Iwane AH, Yanagida T, Imai H, Yu-Lee LY, Schroer T, Wynshaw-Boris A and Hirotsune S

    Department of Genetic Disease Research, Graduate School of Medicine, Osaka City University, Osaka, Japan.

    Lissencephaly is a devastating neurological disorder caused by defective neuronal migration. The LIS1 (or PAFAH1B1) gene was identified as the gene mutated in lissencephaly patients, and was found to regulate cytoplasmic dynein function and localization. In particular, LIS1 is essential for anterograde transport of cytoplasmic dynein as a part of the cytoplasmic dynein-LIS1-microtubule complex in a kinesin-1-dependent manner. However, the underlying mechanism by which a cytoplasmic dynein-LIS1-microtubule complex binds kinesin-1 is unknown. Here, we report that mNUDC (mammalian NUDC) interacts with kinesin-1 and is required for the anterograde transport of a cytoplasmic dynein complex by kinesin-1. mNUDC is also required for anterograde transport of a dynactin-containing complex. Inhibition of mNUDC severely suppressed anterograde transport of distinct cytoplasmic dynein and dynactin complexes, whereas motility of kinesin-1 remained intact. Reconstruction experiments clearly demonstrated that mNUDC mediates the interaction of the dynein or dynactin complex with kinesin-1 and supports their transport by kinesin-1. Our findings have uncovered an essential role of mNUDC for anterograde transport of dynein and dynactin by kinesin-1.

    Funded by: NICHD NIH HHS: HD47380, R01 HD047380; NINDS NIH HHS: NS41030, R01 NS041030

    The EMBO journal 2010;29;3;517-31

  • HDAC1 nuclear export induced by pathological conditions is essential for the onset of axonal damage.

    Kim JY, Shen S, Dietz K, He Y, Howell O, Reynolds R and Casaccia P

    Graduate Program in Neuroscience at the Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.

    Histone deacetylase 1 (HDAC1) is a nuclear enzyme involved in transcriptional repression. We detected cytosolic HDAC1 in damaged axons in brains of humans with multiple sclerosis and of mice with cuprizone-induced demyelination, in ex vivo models of demyelination and in cultured neurons exposed to glutamate and tumor necrosis factor-alpha. Nuclear export of HDAC1 was mediated by the interaction with the nuclear receptor CRM-1 and led to impaired mitochondrial transport. The formation of complexes between exported HDAC1 and members of the kinesin family of motor proteins hindered the interaction with cargo molecules, thereby inhibiting mitochondrial movement and inducing localized beading. This effect was prevented by inhibiting HDAC1 nuclear export with leptomycin B, treating neurons with pharmacological inhibitors of HDAC activity or silencing HDAC1 but not other HDAC isoforms. Together these data identify nuclear export of HDAC1 as a critical event for impaired mitochondrial transport in damaged neurons.

    Funded by: Medical Research Council: G0700356; NINDS NIH HHS: R01 NS-42925, R01 NS042925, R01 NS042925-07, R01 NS042925-07S1

    Nature neuroscience 2010;13;2;180-9

  • Tight functional coupling of kinesin-1A and dynein motors in the bidirectional transport of neurofilaments.

    Uchida A, Alami NH and Brown A

    Center for Molecular Neurobiology and Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA.

    We have tested the hypothesis that kinesin-1A (formerly KIF5A) is an anterograde motor for axonal neurofilaments. In cultured sympathetic neurons from kinesin-1A knockout mice, we observed a 75% reduction in the frequency of both anterograde and retrograde neurofilament movement. This transport defect could be rescued by kinesin-1A, and with successively decreasing efficacy by kinesin-1B and kinesin-1C. In wild-type neurons, headless mutants of kinesin-1A and kinesin-1C inhibited both anterograde and retrograde movement in a dominant-negative manner. Because dynein is thought to be the retrograde motor for axonal neurofilaments, we investigated the effect of dynein inhibition on anterograde and retrograde neurofilament transport. Disruption of dynein function by using RNA interference, dominant-negative approaches, or a function-blocking antibody also inhibited both anterograde and retrograde neurofilament movement. These data suggest that kinesin-1A is the principal but not exclusive anterograde motor for neurofilaments in these neurons, that there may be some functional redundancy among the kinesin-1 isoforms with respect to neurofilament transport, and that the activities of the anterograde and retrograde neurofilament motors are tightly coordinated.

    Funded by: NINDS NIH HHS: P30 NS045758, P30-NS045758, R01 NS038526, R01 NS038526-11A1, R01-NS38526

    Molecular biology of the cell 2009;20;23;4997-5006

  • Self-organization of MTOCs replaces centrosome function during acentrosomal spindle assembly in live mouse oocytes.

    Schuh M and Ellenberg J

    Gene Expression Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Germany.

    Chromosome segregation in mammalian oocytes is driven by a microtubule spindle lacking centrosomes. Here, we analyze centrosome-independent spindle assembly by quantitative high-resolution confocal imaging in live maturing mouse oocytes. We show that spindle assembly proceeds by the self-organization of over 80 microtubule organizing centers (MTOCs) that form de novo from a cytoplasmic microtubule network in prophase and that functionally replace centrosomes. Initially distributed throughout the ooplasm, MTOCs congress at the center of the oocyte, where they contribute to a massive, Ran-dependent increase of the number of microtubules after nuclear envelope breakdown and to the individualization of clustered chromosomes. Through progressive MTOC clustering and activation of kinesin-5, the multipolar MTOC aggregate self-organizes into a bipolar intermediate, which then elongates and thereby establishes chromosome biorientation. Finally, a stable barrel-shaped acentrosomal metaphase spindle with oscillating chromosomes and astral-like microtubules forms that surprisingly exhibits key properties of a centrosomal spindle.

    Cell 2007;130;3;484-98

  • BGEM: an in situ hybridization database of gene expression in the embryonic and adult mouse nervous system.

    Magdaleno S, Jensen P, Brumwell CL, Seal A, Lehman K, Asbury A, Cheung T, Cornelius T, Batten DM, Eden C, Norland SM, Rice DS, Dosooye N, Shakya S, Mehta P and Curran T

    Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States.

    Funded by: NINDS NIH HHS: 5R37NS036558, N01-NS-0-2331, R37 NS036558

    PLoS biology 2006;4;4;e86

  • Molecular basis of dystrobrevin interaction with kinesin heavy chain: structural determinants of their binding.

    Ceccarini M, Torreri P, Lombardi DG, Macchia G, Macioce P and Petrucci TC

    Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. mceccarini@iss.it

    Dystrobrevins are a family of widely expressed dystrophin-associated proteins that comprises alpha and beta isoforms and displays significant sequence homology with several protein-binding domains of the dystrophin C-terminal region. The complex distribution of the multiple dystrobrevin isoforms suggests that the variability of their composition may be important in mediating their function. We have recently identified kinesin as a novel dystrobrevin-interacting protein and localized the dystrobrevin-binding site on the cargo-binding domain of neuronal kinesin heavy chain (Kif5A). In the present study, we assessed the kinetics of the dystrobrevin-Kif5A interaction by quantitative pull-down assay and surface plasmon resonance (SPR) analysis and found that beta-dystrobrevin binds to kinesin with high affinity (K(D) approximately 40 nM). Comparison of the sensorgrams obtained with alpha and beta-dystrobrevin at the same concentration of analyte showed a lower affinity of alpha compared to that of beta-dystrobrevin, despite their functional domain homology and about 70% sequence identity. Analysis of the contribution of single dystrobrevin domains to the interaction revealed that the deletion of either the ZZ domain or the coiled-coil region decreased the kinetics of the interaction, suggesting that the tertiary structure of dystrobrevin may play a role in regulating the interaction of dystrobrevin with kinesin. In order to understand if structural changes induced by post-translational modifications could affect dystrobrevin affinity for kinesin, we phosphorylated beta-dystrobrevin in vitro and found that it showed reduced binding capacity towards kinesin. The interaction between the adaptor/scaffolding protein dystrobrevin and the motor protein kinesin may play a role in the transport and targeting of components of the dystrophin-associated protein complex to specific sites in the cell, with the differences in the binding properties of dystrobrevin isoforms reflecting their functional diversity within the same cell type. Phosphorylation events could have a regulatory role in this context.

    Journal of molecular biology 2005;354;4;872-82

  • Coordinated transport of phosphorylated amyloid-beta precursor protein and c-Jun NH2-terminal kinase-interacting protein-1.

    Muresan Z and Muresan V

    Department of Physiology and Biophysics, Case School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. zoia.muresan@case.edu

    The transmembrane protein amyloid-beta precursor protein (APP) and the vesicle-associated protein c-Jun NH(2)-terminal kinase-interacting protein-1 (JIP-1) are transported into axons by kinesin-1. Both proteins may bind to kinesin-1 directly and can be transported separately. Because JIP-1 and APP can interact, kinesin-1 may recruit them as a complex, enabling their cotransport. In this study, we tested whether APP and JIP-1 are transported together or separately on different vesicles. We found that, within the cellular context, JIP-1 preferentially interacts with Thr(668)-phosphorylated APP (pAPP), compared with nonphosphorylated APP. In neurons, JIP-1 colocalizes with vesicles containing pAPP and is excluded from those containing nonphosphorylated APP. The accumulation of JIP-1 and pAPP in neurites requires kinesin-1, and the expression of a phosphomimetic APP mutant increases JIP-1 transport. Down-regulation of JIP-1 by small interfering RNA specifically impairs transport of pAPP, with no effect on the trafficking of nonphosphorylated APP. These results indicate that the phosphorylation of APP regulates the formation of a pAPP-JIP-1 complex that accumulates in neurites independent of nonphosphorylated APP.

    Funded by: NIA NIH HHS: AG08012, P50 AG008012; NIGMS NIH HHS: 5R01GM068596-02, R01 GM068596

    The Journal of cell biology 2005;171;4;615-25

  • The ciliary rootlet interacts with kinesin light chains and may provide a scaffold for kinesin-1 vesicular cargos.

    Yang J and Li T

    The Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA. jun_yang@meei.harvard.edu

    The ciliary rootlet is a large striated fibrous network originating from basal bodies in ciliated cells. To explore its postulated role in intracellular transport, we investigated the interaction between kinesin light chains (KLCs) and rootletin, the structural component of ciliary rootlets. We show here that KLCs directly interact with rootletin and are located along ciliary rootlets. Their interactions are mediated by the heptad repeats of KLCs. Further studies found that these interactions tethered kinesin heavy chains along ciliary rootlets. However, the ciliary rootlet-bound kinesin-1 did not recruit microtubules or move along ciliary rootlets. Additionally, amyloid precursor protein (APP; a kinesin-1 vesicular cargo receptor) and presenilin 1 (a presumed cargo of APP/kinesin-1) were found to be enriched along the rootletin fibers, suggesting that the interaction between ciliary rootlets and kinesin-1 recruits APP and presenilin 1 along ciliary rootlets. These findings indicate that ciliary rootlets may provide a scaffold for kinesin-1 vesicular cargos and, thus, play a role in the intracellular transport in ciliated cells.

    Funded by: NEI NIH HHS: EY14104, EY14426, P30 EY014104, R01 EY014226

    Experimental cell research 2005;309;2;379-89

  • The KIF3 motor transports N-cadherin and organizes the developing neuroepithelium.

    Teng J, Rai T, Tanaka Y, Takei Y, Nakata T, Hirasawa M, Kulkarni AB and Hirokawa N

    Department of Cell Biology and Anatomy, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

    In the developing brain, the organization of the neuroepithelium is maintained by a critical balance between proliferation and cell-cell adhesion of neural progenitor cells. The molecular mechanisms that underlie this are still largely unknown. Here, through analysis of a conditional knockout mouse for the Kap3 gene, we show that post-Golgi transport of N-cadherin by the KIF3 molecular motor complex is crucial for maintaining this balance. N-cadherin and beta-catenin associate with the KIF3 complex by co-immunoprecipitation, and colocalize with KIF3 in cells. Furthermore, in KAP3-deficient cells, the subcellular localization of N-cadherin was disrupted. Taken together, these results suggest a potential tumour-suppressing activity for this molecular motor.

    Nature cell biology 2005;7;5;474-82

  • Synapsin and synaptic vesicle protein expression during embryonic and post-natal lens fiber cell differentiation.

    Frederikse PH, Yun E, Kao HT, Zigler JS, Sun Q and Qazi AS

    Department of Pharmacology & Physiology, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA. frederph@umdnj.edu

    Purpose: Reorganization of cytoskeleton and membrane biogenesis are dynamically coordinated during lens fiber cell differentiation and development to produce an organ with precise dimensions and optical properties. Cargo vesicle trafficking is fundamental to cell elongation and has also been implicated in degenerative disease mechanisms. Alzheimer precursor protein (AbetaPP) acts with kinesin, synapsin, and synaptic vesicle proteins to mediate cargo vesicle transport and membrane fusion in neurons. In our previous studies we demonstrated that AbetaPP is also a key element in lens fiber cell formation, and in early-onset cataract that occurs along with early-onset Alzheimer disease in Down syndrome. In the present study we examine lens expression and regulation of a complement of genes associated with cargo and synaptic vesicle transport in neurons.

    Methods: RT-PCR, immunoblot, and immunohistochemical methods were used to characterize expression of AbetaPP and kinesin associated motor proteins, synapsins, and synaptic vesicle proteins in mouse and rat embryonic, post-natal, and adult lenses. Phospho-specific anti-synapsin antibodies were used to determine the distributions of site-1 phosphorylated and dephosphorylated synapsin protein.

    Results: We demonstrate that a substantial complement of cargo and synaptic vesicle proteins involved in AbetaPP mediated vesicle transport are expressed in lenses along the anterior-posterior axis of fiber cells in embryonic and adult lenses, consistent with vesicles, actin filaments, and neuron-like arrangement of microtubules in lenses shown by others. We identify temporal regulation of synapsins I, II, and III during embryonic and post-natal lens development consistent with their roles in neurons. Regulation of vesicle cytoskeleton attachment, actin polymerization, and the capacity to stimulate cell differentiation by synapsins are governed in large part by phosphorylation at a conserved Ser9 residue (site-1). We demonstrate discrete distributions of Ser9 phospho- and dephospho-synapsins along the axial length of rapidly elongating embryonic lens fiber cells, and decreased levels of site-1 phosphorylated synapsins in adult lenses.

    Conclusions: The present findings demonstrate several fundamental parallels between lens and neuron vesicle trafficking cell biology and development, and suggest that more extensive AbetaPP related vesicle trafficking disease mechanisms may be shared by lens and brain.

    Molecular vision 2004;10;794-804

  • The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

    Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Morrin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J and MGC Project Team

    The National Institutes of Health's Mammalian Gene Collection (MGC) project was designed to generate and sequence a publicly accessible cDNA resource containing a complete open reading frame (ORF) for every human and mouse gene. The project initially used a random strategy to select clones from a large number of cDNA libraries from diverse tissues. Candidate clones were chosen based on 5'-EST sequences, and then fully sequenced to high accuracy and analyzed by algorithms developed for this project. Currently, more than 11,000 human and 10,000 mouse genes are represented in MGC by at least one clone with a full ORF. The random selection approach is now reaching a saturation point, and a transition to protocols targeted at the missing transcripts is now required to complete the mouse and human collections. Comparison of the sequence of the MGC clones to reference genome sequences reveals that most cDNA clones are of very high sequence quality, although it is likely that some cDNAs may carry missense variants as a consequence of experimental artifact, such as PCR, cloning, or reverse transcriptase errors. Recently, a rat cDNA component was added to the project, and ongoing frog (Xenopus) and zebrafish (Danio) cDNA projects were expanded to take advantage of the high-throughput MGC pipeline.

    Funded by: PHS HHS: N01-C0-12400

    Genome research 2004;14;10B;2121-7

  • Kinesin transports RNA: isolation and characterization of an RNA-transporting granule.

    Kanai Y, Dohmae N and Hirokawa N

    Department of Cell Biology and Anatomy, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

    RNA transport is an important and fundamental event for local protein synthesis, especially in neurons. RNA is transported as large granules, but little is known about them. Here, we isolated a large RNase-sensitive granule (size: 1000S approximately) as a binding partner of conventional kinesin (KIF5). We identified a total of 42 proteins with mRNAs for CaMKIIalpha and Arc in the granule. Seventeen of the proteins (hnRNP-U, Pur alpha and beta, PSF, DDX1, DDX3, SYNCRIP, TLS, NonO, HSPC117, ALY, CGI-99, staufen, three FMRPs, and EF-1alpha) were extensively investigated, including their classification, binding combinations, and necessity for the "transport" of RNA. These proteins and the mRNAs were colocalized to the kinesin-associated granules in dendrites. The granules moved bidirectionally, and the distally directed movement was enhanced by the overexpression of KIF5 and reduced by its functional blockage. Thus, kinesin transports RNA via this granule in dendrites coordinately with opposite motors, such as dynein.

    Neuron 2004;43;4;513-25

  • GenePaint.org: an atlas of gene expression patterns in the mouse embryo.

    Visel A, Thaller C and Eichele G

    Max Planck Institute of Experimental Endocrinology, Feodor-Lynen-Strasse 7, D-30625 Hannover, Germany.

    High-throughput instruments were recently developed to determine gene expression patterns on tissue sections by RNA in situ hybridization. The resulting images of gene expression patterns, chiefly of E14.5 mouse embryos, are accessible to the public at http://www.genepaint.org. This relational database is searchable for gene identifiers and RNA probe sequences. Moreover, patterns and intensity of expression in approximately 100 different embryonic tissues are annotated and can be searched using a standardized catalog of anatomical structures. A virtual microscope tool, the Zoom Image Server, was implemented in GenePaint.org and permits interactive zooming and panning across approximately 15,000 high-resolution images.

    Nucleic acids research 2004;32;Database issue;D552-6

  • Beta-dystrobrevin interacts directly with kinesin heavy chain in brain.

    Macioce P, Gambara G, Bernassola M, Gaddini L, Torreri P, Macchia G, Ramoni C, Ceccarini M and Petrucci TC

    Laboratory of Cell Biology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. macioce@iss.it

    Beta-dystrobrevin, a member of the dystrobrevin protein family, is a dystrophin-related and -associated protein restricted to non-muscle tissues and is highly expressed in kidney, liver and brain. Dystrobrevins are now thought to play an important role in intracellular signal transduction, in addition to providing a membrane scaffold in muscle, but the precise role of beta-dystrobrevin has not yet been determined. To study beta-dystrobrevin's function in brain, we used the yeast two-hybrid approach to look for interacting proteins. Four overlapping clones were identified that encoded Kif5A, a neuronal member of the Kif5 family of proteins that consists of the heavy chains of conventional kinesin. A direct interaction of beta-dystrobrevin with Kif5A was confirmed by in vitro and in vivo association assays. Co-immunoprecipitation with a monoclonal kinesin heavy chain antibody precipitated both alpha- and beta-dystrobrevin, indicating that this interaction is not restricted to the beta-dystrobrevin isoform. The site for Kif5A binding to beta-dystrobrevin was localized in a carboxyl-terminal region that seems to be important in heavy chain-mediated kinesin interactions and is highly homologous in all three Kif5 isoforms, Kif5A, Kif5B and Kif5C. Pull-down and immunofluorescence experiments also showed a direct interaction between beta-dystrobrevin and Kif5B. Our findings suggest a novel function for dystrobrevin as a motor protein receptor that might play a major role in the transport of components of the dystrophin-associated protein complex to specific sites in the cell.

    Journal of cell science 2003;116;Pt 23;4847-56

  • Abnormal neurofilament transport caused by targeted disruption of neuronal kinesin heavy chain KIF5A.

    Xia CH, Roberts EA, Her LS, Liu X, Williams DS, Cleveland DW and Goldstein LS

    Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093-0683, USA.

    To test the hypothesis that fast anterograde molecular motor proteins power the slow axonal transport of neurofilaments (NFs), we used homologous recombination to generate mice lacking the neuronal-specific conventional kinesin heavy chain, KIF5A. Because null KIF5A mutants die immediately after birth, a synapsin-promoted Cre-recombinase transgene was used to direct inactivation of KIF5A in neurons postnatally. Three fourths of such mutant mice exhibited seizures and death at around 3 wk of age; the remaining animals survived to 3 mo or longer. In young mutant animals, fast axonal transport appeared to be intact, but NF-H, as well as NF-M and NF-L, accumulated in the cell bodies of peripheral sensory neurons accompanied by a reduction in sensory axon caliber. Older animals also developed age-dependent sensory neuron degeneration, an accumulation of NF subunits in cell bodies and a reduction in axons, loss of large caliber axons, and hind limb paralysis. These data support the hypothesis that a conventional kinesin plays a role in the microtubule-dependent slow axonal transport of at least one cargo, the NF proteins.

    Funded by: NEI NIH HHS: R01 EY007042; NIGMS NIH HHS: GM35252, R01 GM035252; NINDS NIH HHS: R37 NS027036

    The Journal of cell biology 2003;161;1;55-66

  • BayGenomics: a resource of insertional mutations in mouse embryonic stem cells.

    Stryke D, Kawamoto M, Huang CC, Johns SJ, King LA, Harper CA, Meng EC, Lee RE, Yee A, L'Italien L, Chuang PT, Young SG, Skarnes WC, Babbitt PC and Ferrin TE

    Department of Pharmaceutical Chemistry, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.

    The BayGenomics gene-trap resource (http://baygenomics.ucsf.edu) provides researchers with access to thousands of mouse embryonic stem (ES) cell lines harboring characterized insertional mutations in both known and novel genes. Each cell line contains an insertional mutation in a specific gene. The identity of the gene that has been interrupted can be determined from a DNA sequence tag. Approximately 75% of our cell lines contain insertional mutations in known mouse genes or genes that share strong sequence similarities with genes that have been identified in other organisms. These cell lines readily transmit the mutation to the germline of mice and many mutant lines of mice have already been generated from this resource. BayGenomics provides facile access to our entire database, including sequence tags for each mutant ES cell line, through the World Wide Web. Investigators can browse our resource, search for specific entries, download any portion of our database and BLAST sequences of interest against our entire set of cell line sequence tags. They can then obtain the mutant ES cell line for the purpose of generating knockout mice.

    Funded by: NCRR NIH HHS: P41 RR001081, P41 RR01081; NHLBI NIH HHS: U01 HL066621, U01 HL66621

    Nucleic acids research 2003;31;1;278-81

  • A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10).

    Reid E, Kloos M, Ashley-Koch A, Hughes L, Bevan S, Svenson IK, Graham FL, Gaskell PC, Dearlove A, Pericak-Vance MA, Rubinsztein DC and Marchuk DA

    Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, United Kingdom. ereid@hgmp.mrc.ac.uk

    We have identified a missense mutation in the motor domain of the neuronal kinesin heavy chain gene KIF5A, in a family with hereditary spastic paraplegia. The mutation occurs in the family in which the SPG10 locus was originally identified, at an invariant asparagine residue that, when mutated in orthologous kinesin heavy chain motor proteins, prevents stimulation of the motor ATPase by microtubule-binding. Mutation of kinesin orthologues in various species leads to phenotypes resembling hereditary spastic paraplegia. The conventional kinesin motor powers intracellular movement of membranous organelles and other macromolecular cargo from the neuronal cell body to the distal tip of the axon. This finding suggests that the underlying pathology of SPG10 and possibly of other forms of hereditary spastic paraplegia may involve perturbation of neuronal anterograde (or retrograde) axoplasmic flow, leading to axonal degeneration, especially in the longest axons of the central nervous system.

    Funded by: NINDS NIH HHS: P01 NS 26630, P01 NS026630

    American journal of human genetics 2002;71;5;1189-94

  • Glutamate-receptor-interacting protein GRIP1 directly steers kinesin to dendrites.

    Setou M, Seog DH, Tanaka Y, Kanai Y, Takei Y, Kawagishi M and Hirokawa N

    Department of Cell Biology and Anatomy, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.

    In cells, molecular motors operate in polarized sorting of molecules, although the steering mechanisms of motors remain elusive. In neurons, the kinesin motor conducts vesicular transport such as the transport of synaptic vesicle components to axons and of neurotransmitter receptors to dendrites, indicating that vesicles may have to drive the motor for the direction to be correct. Here we show that an AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate) receptor subunit--GluR2-interacting protein (GRIP1)--can directly interact and steer kinesin heavy chains to dendrites as a motor for AMPA receptors. As would be expected if this complex is functional, both gene targeting and dominant negative experiments of heavy chains of mouse kinesin showed abnormal localization of GRIP1. Moreover, expression of the kinesin-binding domain of GRIP1 resulted in accumulation of the endogenous kinesin predominantly in the somatodendritic area. This pattern was different from that generated by the overexpression of the kinesin-binding scaffold protein JSAP1 (JNK/SAPK-associated protein-1, also known as Mapk8ip3), which occurred predominantly in the somatoaxon area. These results indicate that directly binding proteins can determine the traffic direction of a motor protein.

    Nature 2002;417;6884;83-7

  • Identification of quantitative trait Loci that affect aggressive behavior in mice.

    Brodkin ES, Goforth SA, Keene AH, Fossella JA and Silver LM

    Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.

    Despite the previous development of single-gene knock-out mice that exhibit alterations in aggressive behavior, very little progress has been made toward identifying the natural gene variants (alleles) that contribute to individual or strain differences in aggression. Whereas most inbred mouse strains show an intermediate level of inter-male aggression in the resident-intruder or dangler behavioral tests, NZB/B1NJ mice are extremely aggressive and A/J mice are extremely unaggressive. We took advantage of the large phenotypic difference between these strains and used an outcross-backcross breeding protocol and a genome-wide scan to identify aggression quantitative trait loci (QTLs) on distal chromosome 10 (Aggr1; p = 6 x 10(-7)) and proximal chromosome X (Aggr2; p = 2.14 x 10(-5)). Candidate genes for Aggr1 and Aggr2, respectively, include the diacylglycerol kinase alpha subunit gene (Dagk1) and the glutamate receptor subunit AMPA3 gene (Gria3). This is the first report of significant aggression QTLs established through a genome-wide scan in any mammal. The mapping of these QTLs is a step toward the definitive identification of mouse alleles that affect aggression and may lead, ultimately, to the discovery of homologous alleles that affect individual differences in aggression within other mammalian species.

    Funded by: NICHD NIH HHS: R37 HD20275-17; NIMH NIH HHS: 1 F32 MH12203-01

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2002;22;3;1165-70

  • Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta.

    Zhao C, Takita J, Tanaka Y, Setou M, Nakagawa T, Takeda S, Yang HW, Terada S, Nakata T, Takei Y, Saito M, Tsuji S, Hayashi Y and Hirokawa N

    Department of Cell Biology and Anatomy, University of Tokyo, Hongo, Tokyo 113-0033, Japan.

    The kinesin superfamily motor protein KIF1B has been shown to transport mitochondria. Here, we describe an isoform of KIF1B, KIF1Bbeta, that is distinct from KIF1B in its cargo binding domain. KIF1B knockout mice die at birth from apnea due to nervous system defects. Death of knockout neurons in culture can be rescued by expression of the beta isoform. The KIF1B heterozygotes have a defect in transporting synaptic vesicle precursors and suffer from progressive muscle weakness similar to human neuropathies. Charcot-Marie-Tooth disease type 2A was previously mapped to an interval containing KIF1B. We show that CMT2A patients contain a loss-of-function mutation in the motor domain of the KIF1B gene. This is clear indication that defects in axonal transport due to a mutated motor protein can underlie human peripheral neuropathy.

    Cell 2001;105;5;587-97

  • KIF5C, a novel neuronal kinesin enriched in motor neurons.

    Kanai Y, Okada Y, Tanaka Y, Harada A, Terada S and Hirokawa N

    Department of Cell Biology and Anatomy, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

    Kinesin superfamily proteins (KIFs) are the molecular motors conveying cargos along microtubules. KIF5s, the heavy chains of conventional kinesin (KHC), are originally identified members of KIFs, and neuronal KIF5A and ubiquitous KIF5B have been identified so far. In the present work, we cloned a novel member of KIF5, KIF5C, and generated specific antibodies against three KIF5s to investigate their distribution and functions. KIF5A showed pan-neuronal distribution in the nervous system. KIF5B showed a glial cell distribution pattern in general; however, interestingly, its expression was strongly upregulated in axon-elongating neurons, such as olfactory primary neurons and mossy fibers. KIF5C was also a neuronal KIF5 like KIF5A but was highly expressed in lower motor neurons in 2-week-old or older mice, suggesting its important roles in the maintenance of motor neurons rather than in their formation, such as axonal elongation. Because a large part of KIF5s in adult motor neurons were expected to be KIF5C, we generated mice lacking the kif5C gene to investigate the functions of KIF5C in neurons in living animals. The mutant mice showed smaller brain size but were viable and did not show gross changes in the nervous system. Closer examinations revealed the relative loss of motor neurons to sensory neurons. Because three KIF5s showed high similarity in the amino acid sequence, could rescue the KIF5B mutant cells, and could form heterodimers, we think that there are functional redundancy among the three KIF5s and that KIF5A and KIF5B prevented the KIF5C null mice from the severe phenotype.

    Funded by: NICHD NIH HHS: N01-HD-2-3144

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2000;20;17;6374-84

  • Defective kinesin heavy chain behavior in mouse kinesin light chain mutants.

    Rahman A, Kamal A, Roberts EA and Goldstein LS

    Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California 92093-0683, USA.

    Conventional kinesin, kinesin-I, is a heterotetramer of two kinesin heavy chain (KHC) subunits (KIF5A, KIF5B, or KIF5C) and two kinesin light chain (KLC) subunits. While KHC contains the motor activity, the role of KLC remains unknown. It has been suggested that KLC is involved in either modulation of KHC activity or in cargo binding. Previously, we characterized KLC genes in mouse (Rahman, A., D.S. Friedman, and L.S. Goldstein. 1998. J. Biol. Chem. 273:15395-15403). Of the two characterized gene products, KLC1 was predominant in neuronal tissues, whereas KLC2 showed a more ubiquitous pattern of expression. To define the in vivo role of KLC, we generated KLC1 gene-targeted mice. Removal of functional KLC1 resulted in significantly smaller mutant mice that also exhibited pronounced motor disabilities. Biochemical analyses demonstrated that KLC1 mutant mice have a pool of KIF5A not associated with any known KLC subunit. Immunofluorescence studies of sensory and motor neuron cell bodies in KLC1 mutants revealed that KIF5A colocalized aberrantly with the peripheral cis-Golgi marker giantin in mutant cells. Striking changes and aberrant colocalization were also observed in the intracellular distribution of KIF5B and beta'-COP, a component of COP1 coatomer. Taken together, these data best support models that suggest that KLC1 is essential for proper KHC activation or targeting.

    The Journal of cell biology 1999;146;6;1277-88

  • Chromosomal localization reveals three kinesin heavy chain genes in mouse.

    Xia Ch, Rahman A, Yang Z and Goldstein LS

    Division of Cellular and Molecular Medicine, Department of Pharmacology, University of California at San Diego, 9500 Gilman Drive, La Jolla, California, 92093-0683, USA.

    Kinesin-related proteins constitute a superfamily of microtubule-dependent motors that play important roles in organelle transport and cell division. These molecules share a conserved motor region of approximately 340 amino acids, which is attached to diverse "tail" or cargo-binding domains. The kinesin superfamily was first defined by kinesin heavy chain, which is the principal component of "true" kinesin. Invertebrates appear to possess only a single gene encoding kinesin heavy chain. Mammals appear to have two or more genes encoding kinesin heavy chain, although the precise situation has been unclear. Here we definitively demonstrate that mouse has three kinesin heavy chain genes, Kif5a, Kif5b, and Kif5c. Kif5a, Kif5b, and Kif5c map to mouse chromosomes 10, 18, and 2; Kif5a and Kif5c appear to be expressed only in neuronal tissues by Northern blot analysis while Kif5b appears to be ubiquitous in its expression.

    Genomics 1998;52;2;209-13

  • Genetic mapping of 262 loci derived from expressed sequences in a murine interspecific cross using single-strand conformational polymorphism analysis.

    Brady KP, Rowe LB, Her H, Stevens TJ, Eppig J, Sussman DJ, Sikela J and Beier DR

    Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

    We have demonstrated previously that noncoding sequences of genes are a robust source of polymorphisms between mouse species when tested using single-strand conformation polymorphism (SSCP) analysis, and that these polymorphisms are useful for genetic mapping. In this report we demonstrate that presumptive 3'-untranslated region sequence obtained from expressed sequence tags (ESTs) can be analyzed in a similar fashion, and we have used this approach to map 262 loci using an interspecific backcross. These results demonstrate SSCP analysis of genes or ESTs is a simple and efficient means for the genetic localization of transcribed sequences, and is furthermore an approach that is applicable to any system for which there is sufficient sequence polymorphism.

    Funded by: NHGRI NIH HHS: HG00941, HG00951

    Genome research 1997;7;11;1085-93

  • Identification and classification of 16 new kinesin superfamily (KIF) proteins in mouse genome.

    Nakagawa T, Tanaka Y, Matsuoka E, Kondo S, Okada Y, Noda Y, Kanai Y and Hirokawa N

    Department of Cell Biology and Anatomy, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113, Japan.

    KIF (kinesin superfamily) proteins are microtubule-dependent molecular motors that play important roles in intracellular transport and cell division. The extent to which KIFs are involved in various transporting phenomena, as well as their regulation mechanism, are unknown. The identification of 16 new KIFs in this report doubles the existing number of KIFs known in the mouse. Conserved nucleotide sequences in the motor domain were amplified by PCR using cDNAs of mouse nervous tissue, kidney, and small intestine as templates. The new KIFs were studied with respect to their expression patterns in different tissues, chromosomal location, and molecular evolution. Our results suggest that (i) there is no apparent tendency among related subclasses of KIFs of cosegregation in chromosomal mapping, and (ii) according to their tissue distribution patterns, KIFs can be divided into two classes-i.e., ubiquitous and specific tissue-dominant. Further characterization of KIFs may elucidate unknown fundamental phenomena underlying intracellular transport. Finally, we propose a straightforward nomenclature system for the members of the mouse kinesin superfamily.

    Proceedings of the National Academy of Sciences of the United States of America 1997;94;18;9654-9

  • Identification and partial characterization of mitotic centromere-associated kinesin, a kinesin-related protein that associates with centromeres during mitosis.

    Wordeman L and Mitchison TJ

    Department of Physiology and Biophysics, University of Washington, Seattle 98195.

    Using antipeptide antibodies to conserved regions of the kinesin motor domain, we cloned a kinesin-related protein that associates with the centromere region of mitotic chromosomes. We call the protein MCAK, for mitotic centromere-associated kinesin. MCAK appears concentrated on centromeres at prophase and persists until telophase, after which time the localization disperses. It is found throughout the centromere region and between the kinetochore plates of isolated mitotic CHO chromosomes, in contrast to two other kinetochore-associated microtubule motors: cytoplasmic dynein and CENP-E (Yen et al., 1992), which are closer to the outer surface of the kinetochore plates. Sequence analysis shows MCAK to be a kinesin-related protein with the motor domain located in the center of the protein. It is 60-70% similar to kif2, a kinesin-related protein originally cloned from mouse brain with a centrally located motor domain (Aizawa et al., 1992). MCAK protein is present in interphase and mitotic CHO cells and is transcribed as a single 3.4-kb message.

    Funded by: NCI NIH HHS: CA-09270; NIGMS NIH HHS: GM-39565

    The Journal of cell biology 1995;128;1-2;95-104

  • KIF1B, a novel microtubule plus end-directed monomeric motor protein for transport of mitochondria.

    Nangaku M, Sato-Yoshitake R, Okada Y, Noda Y, Takemura R, Yamazaki H and Hirokawa N

    Department of Anatomy and Cell Biology School of Medicine, University of Tokyo, Japan.

    To further elucidate the mechanism of organelle transport, we cloned a novel member of the mouse kinesin superfamily, KIF1B. This N-terminal-type motor protein is expressed ubiquitously in various kinds of tissues. In situ hybridization revealed that KIF1B is expressed abundantly in differentiated nerve cells. Interestingly, K1F1B works as a monomer, having a microtubule plus end-directed motility. Our rotary shadowing electron microscopy revealed mostly single globular structures. Immunocytochemically, KIF1B was colocalized with mitochondria in vivo. Furthermore, a subcellular fractionation study showed that KIF1B was concentrated in the mitochondrial fraction, and purified K1F1B could transport mitochondria along microtubules in vitro. These data strongly suggested that KIF1B works as a monomeric motor for anterograde transport of mitochondria.

    Cell 1994;79;7;1209-20

  • Identification of Evi-3, a novel common site of retroviral integration in mouse AKXD B-cell lymphomas.

    Justice MJ, Morse HC, Jenkins NA and Copeland NG

    Division of Biology, Kansas State University, Manhattan 66506.

    We have identified a novel common site of ecotropic viral integration called ecotropic viral integration site 3 (Evi-3) in B-cell lineage lymphomas of the AKXD recombinant inbred strains of mice. A number of virally induced pre-B-, B-, myeloid, and T-cell lymphomas were screened for viral rearrangements at Evi-3; rearrangements were found in pre-B- and B-cell lymphomas but not in other hematopoietic tumors. Genetic mapping studies localized Evi-3 to mouse chromosome 18, distinct from proto-oncogene and common viral integration loci identified previously in the mouse. Each proviral integration at Evi-3 is contained within a 200-bp region that lies inside a CpG island. All but one of the proviruses have integrated in the same 5'-to-3' transcriptional orientation. Transcripts from Evi-3 are expressed in a developmentally regulated manner in B cells. Taken together, these data suggest that Evi-3 represents a novel proto-oncogene involved in mouse B-cell lymphomas.

    Funded by: NCI NIH HHS: 5F32CA08853-03, N01-CO-74101; NIAID NIH HHS: N01-AI-72622

    Journal of virology 1994;68;3;1293-300

  • Kinesin family in murine central nervous system.

    Aizawa H, Sekine Y, Takemura R, Zhang Z, Nangaku M and Hirokawa N

    Department of Anatomy and Cell Biology, School of Medicine, University of Tokyo, Japan.

    In neuronal axons, various kinds of membranous components are transported along microtubules bidirectionally. However, only two kinds of mechanochemical motor proteins, kinesin and brain dynein, had been identified as transporters of membranous organelles in mammalian neurons. Recently, a series of genes that encode proteins closely related to kinesin heavy chain were identified in several organisms including Schizosaccharomyces pombe, Aspergillus niddulans, Saccharomyces cerevisiae, Caenorhabditus elegans, and Drosophila. Most of these members of the kinesin family are implicated in mechanisms of mitosis or meiosis. To address the mechanism of intracellular organelle transport at a molecular level, we have cloned and characterized five different members (KIF1-5), that encode the microtubule-associated motor domain homologous to kinesin heavy chain, in murine brain tissue. Homology analysis of amino acid sequence indicated that KIF1 and KIF5 are murine counterparts of unc104 and kinesin heavy chain, respectively, while KIF2, KIF3, and KIF4 are as yet unidentified new species. Complete amino acid sequence of KIF3 revealed that KIF3 consists of NH2-terminal motor domain, central alpha-helical rod domain, and COOH-terminal globular domain. Complete amino acid sequence of KIF2 revealed that KIF2 consists of NH2-terminal globular domain, central motor domain, and COOH-terminal alpha-helical rod domain. This is the first identification of the kinesin-related protein which has its motor domain at the central part in its primary structure. Northern blot analysis revealed that KIF1, KIF3, and KIF5 are expressed almost exclusively in murine brain, whereas KIF2 and KIF4 are expressed in brain as well as in other tissues. All these members of the kinesin family are expressed in the same type of neurons, and thus each one of them may transport its specific organelle in the murine central nervous system.

    The Journal of cell biology 1992;119;5;1287-96

  • A molecular genetic linkage map of mouse chromosome 18 reveals extensive linkage conservation with human chromosomes 5 and 18.

    Justice MJ, Gilbert DJ, Kinzler KW, Vogelstein B, Buchberg AM, Ceci JD, Matsuda Y, Chapman VM, Patriotis C, Makris A et al.

    Mammalian Genetics Laboratory, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Maryland 21702.

    An interspecific backcross between C57BL/6J and Mus spretus was used to generate a molecular genetic linkage map of mouse chromosome 18 that includes 23 molecular markers and spans approximately 86% of the estimated length of the chromosome. The Apc, Camk2a, D18Fcr1, D18Fcr2, D18Leh1, D18Leh2, Dcc, Emb-rs3, Fgfa, Fim-2/Csfmr, Gnal, Grl-1, Grp, Hk-1rs1, Ii, Kns, Lmnb, Mbp, Mcc, Mtv-38, Palb, Pdgfrb, and Tpl-2 genes were mapped relative to each other in one interspecific backcross. A second interspecific backcross and a centromere-specific DNA satellite probe were used to determine the distance of the most proximal chromosome 18 marker to the centromere. The interspecific map extends the known regions of linkage homology between mouse chromosome 18 and human chromosomes 5 and 18 and identifies a new homology segment with human chromosome 10p. It also provides molecular access to many regions of mouse chromosome 18 for the first time.

    Funded by: NCI NIH HHS: 5F32CA08853-03, N01-CO-74101

    Genomics 1992;13;4;1281-8

  • Cloning and expression of a human kinesin heavy chain gene: interaction of the COOH-terminal domain with cytoplasmic microtubules in transfected CV-1 cells.

    Navone F, Niclas J, Hom-Booher N, Sparks L, Bernstein HD, McCaffrey G and Vale RD

    Department of Pharmacology, University of California, San Francisco 94143.

    To understand the interactions between the microtubule-based motor protein kinesin and intracellular components, we have expressed the kinesin heavy chain and its different domains in CV-1 monkey kidney epithelial cells and examined their distributions by immunofluorescence microscopy. For this study, we cloned and sequenced cDNAs encoding a kinesin heavy chain from a human placental library. The human kinesin heavy chain exhibits a high level of sequence identity to the previously cloned invertebrate kinesin heavy chains; homologies between the COOH-terminal domain of human and invertebrate kinesins and the nonmotor domain of the Aspergillus kinesin-like protein bimC were also found. The gene encoding the human kinesin heavy chain also contains a small upstream open reading frame in a G-C rich 5' untranslated region, features that are associated with translational regulation in certain mRNAs. After transient expression in CV-1 cells, the kinesin heavy chain showed both a diffuse distribution and a filamentous staining pattern that coaligned with microtubules but not vimentin intermediate filaments. Altering the number and distribution of microtubules with taxol or nocodazole produced corresponding changes in the localization of the expressed kinesin heavy chain. The expressed NH2-terminal motor and the COOH-terminal tail domains, but not the alpha-helical coiled coil rod domain, also colocalized with microtubules. The finding that both the kinesin motor and tail domains can interact with cytoplasmic microtubules raises the possibility that kinesin could crossbridge and induce sliding between microtubules under certain circumstances.

    Funded by: NIGMS NIH HHS: GM38499, R01 GM038499

    The Journal of cell biology 1992;117;6;1263-75

Gene lists (4)

Gene List Source Species Name Description Gene count
L00000060 G2C Mus musculus BAYES-COLLINS-HUMAN-PSD-CONSENSUS Human cortex PSD consensus (ortho) 748
L00000062 G2C Mus musculus BAYES-COLLINS-MOUSE-PSD-CONSENSUS Mouse cortex PSD consensus 984
L00000070 G2C Mus musculus BAYES-COLLINS-HUMAN-PSD-FULL Human cortex biopsy PSD full list (ortho) 1461
L00000072 G2C Mus musculus BAYES-COLLINS-MOUSE-PSD-FULL Mouse cortex PSD full list 1556
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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