Nobutaka Hirokawa

King Abdulaziz University, Djidda, Makkah, Saudi Arabia

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Publications (330)3134.71 Total impact

  • Tadayuki Ogawa · Nobutaka Hirokawa ·
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    ABSTRACT: Neurons exhibit dynamic structural changes in response to extracellular stimuli. Microtubules (MTs) provide rapid and dramatic cytoskeletal changes within the structural framework. However, the molecular mechanisms and signaling networks underlying MT dynamics remain unknown. Here, we have applied a comprehensive and quantitative phospho-analysis of the MT destabilizer KIF2A to elucidate the regulatory mechanisms of MT dynamics within neurons in response to extracellular signals. Interestingly, we identified two different sets of KIF2A phosphorylation profiles that accelerate (A-type) and brake (B-type) the MT depolymerization activity of KIF2A. Brain-derived neurotrophic factor (BDNF) stimulates PAK1 and CDK5 kinases, which decrease the MT depolymerizing activity of KIF2A through B-type phosphorylation, resulting in enhanced outgrowth of neural processes. In contrast, lysophosphatidic acid (LPA) induces ROCK2 kinase, which suppresses neurite outgrowth from round cells via A-type phosphorylation. We propose that these two mutually exclusive forms of KIF2A phosphorylation differentially regulate neuronal morphogenesis during development.
    Cell Reports 09/2015; 12(11). DOI:10.1016/j.celrep.2015.08.018 · 8.36 Impact Factor
  • Sotaro Ichinose · Tadayuki Ogawa · Nobutaka Hirokawa ·
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    ABSTRACT: A regulated mechanism of cargo loading is crucial for intracellular transport. N-cadherin, a synaptic adhesion molecule that is critical for neuronal function, must be precisely transported to dendritic spines in response to synaptic activity and plasticity. However, the mechanism of activity-dependent cargo loading remains unclear. To elucidate this mechanism, we investigated the activity-dependent transport of N-cadherin via its transporter, KIF3A. First, by comparing KIF3A-bound cargo vesicles with unbound KIF3A, we identified critical KIF3A phosphorylation sites and specific kinases, PKA and CaMKIIa, using quantitative phosphoanalyses. Next, mutagenesis and kinase inhibitor experiments revealed that N-cadherin transport was enhanced via phosphorylation of the KIF3A C terminus, thereby increasing cargo-loading activity. Furthermore, N-cadherin transport was enhanced during homeostatic upregulation of synaptic strength, triggered by chronic inactivation by TTX. We propose the first model of activity-dependent cargo loading, in which phosphorylation of the KIF3A C terminus upregulates the loading and transport of N-cadherin in homeostatic synaptic plasticity. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 09/2015; 87(5):1022-35. DOI:10.1016/j.neuron.2015.08.008 · 15.05 Impact Factor
  • Atena Farkhondeh · Shinsuke Niwa · Yosuke Takei · Nobutaka Hirokawa ·
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    ABSTRACT: An organelle's subcellular localization is closely related to its function. Early endosomes require localization to somatodendritic regions in neurons to enable neuronal morphogenesis, polarized sorting, and signal transduction. However, it is not known how the somatodendritic localization of early endosomes is achieved. Here, we show that the kinesin superfamily protein 16B (KIF16B) is essential for the correct localization of early endosomes in mouse hippocampal neurons. Loss of KIF16B induced the aggregation of early endosomes and perturbed the trafficking and functioning of receptors, including the AMPA and NGF receptors. This defect was rescued by KIF16B, emphasizing the critical functional role of the protein in early endosome and receptor transport. Interestingly, in neurons expressing a KIF16B deletion mutant lacking the second and third coiled-coils of the stalk domain, the early endosomes were mistransported to the axons. Additionally, the binding of the motor domain of KIF16B to microtubules was inhibited by the second and third coiled-coils (inhibitory domain) in an ATP-dependent manner. This suggests that the intramolecular binding we find between the inhibitory domain and motor domain of KIF16B may serve as a switch to control the binding of the motor to microtubules, thereby regulating KIF16B activity. We propose that this novel autoregulatory "stalk inhibition" mechanism underlies the ability of KIF16B to potentiate the selective somatodendritic localization of early endosomes. Copyright © 2015 the authors 0270-6474/15/355067-20$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 03/2015; 35(12):5067-86. DOI:10.1523/JNEUROSCI.4240-14.2015 · 6.34 Impact Factor
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    ABSTRACT: The molecular motor kinesin moves along microtubules using energy from ATP hydrolysis in an initial step coupled with ADP release. In neurons, kinesin-1/KIF5C preferentially binds to the GTP-state microtubules over GDP-state microtubules to selectively enter an axon among many processes; however, because the atomic structure of nucleotide-free KIF5C is unavailable, its molecular mechanism remains unresolved. Here, the crystal structure of nucleotide-free KIF5C and the cryo-electron microscopic structure of nucleotide-free KIF5C complexed with the GTP-state microtubule are presented. The structures illustrate mutual conformational changes induced by interaction between the GTP-state microtubule and KIF5C. KIF5C acquires the 'rigor conformation', where mobile switches I and II are stabilized through L11 and the initial portion of the neck-linker, facilitating effective ADP release and the weak-to-strong transition of KIF5C microtubule affinity. Conformational changes to tubulin strengthen the longitudinal contacts of the GTP-state microtubule in a similar manner to GDP-taxol microtubules. These results and functional analyses provide the molecular mechanism of the preferential binding of KIF5C to GTP-state microtubules. © 2015 The Authors.
    The EMBO Journal 03/2015; 34(9). DOI:10.15252/embj.201490588 · 10.43 Impact Factor
  • Nobutaka Hirokawa · Yosuke Tanaka ·
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    ABSTRACT: Kinesin superfamily proteins (KIFs) largely serve as molecular motors on the microtubule system and transport various cellular proteins, macromolecules, and organelles. These transports are fundamental to cellular logistics, and at times, they directly modulate signal transduction by altering the semantics of informational molecules. In this review, we will summarize recent approaches to the regulation of the transport destinations and to the physiological relevance of the role of these proteins in neuroscience, ciliary functions, and metabolic diseases. Understanding these burning questions will be essential in establishing a new paradigm of cellular functions and disease pathogenesis. Copyright © 2015. Published by Elsevier Inc.
    Experimental Cell Research 02/2015; 334(1). DOI:10.1016/j.yexcr.2015.02.016 · 3.25 Impact Factor
  • Toshihiko Ogura · Hiroaki Yajima · Ryo Nitta · Nobutaka Hirokawa · Chikara Sato ·
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    ABSTRACT: The helix is an important motif in biological architectures. The helical structures of nanoscale proteins are principally determined by three-dimensional (3D) reconstruction from electron micrographs. However, bending or distortion of flexible helices and the low contrast of the images recorded by cryo-electron microscopy, prevent the analysis from reaching high resolution. We have developed a novel helical reconstruction method that overcomes these issues, and present the processing of microtubule images to demonstrate its application. Cropping long helical structures into small square pieces allows bending or distortion of the helices to be accounted for. The initial image-frames are automatically positioned assuming perfect helical symmetry. A simulated annealing (SA)-based algorithm is then used to adjust the framing. This is guided by the contrast of 2D averages, which serve as an accuracy index. After the initial 3D reconstruction, the position and orientation of each average image is iteratively adjusted to give the best match between the input average and the reprojection from the reconstruction. Finally, reconstructions from images recorded at different defocus values, are aligned and averaged to compensate the contrast transfer modulation and improve the resolution. The method successfully determined the structure of a 15-protofilament microtubule. The 8.8 Å resolution (7.8 Å using the 0.143 FSC criterion) attained allows differences between the α- and β- tubulins to be discerned in the absence of a molecular landmark such as microtubule-associated proteins, for the first time by electron microscopy. The SA-based method is applicable to other helical protein complexes and in general to helical structures.
    Journal of Structural Biology 11/2014; 188(2). DOI:10.1016/j.jsb.2014.08.009 · 3.23 Impact Factor
  • Wenxing Yang · Yosuke Tanaka · Miki Bundo · Nobutaka Hirokawa ·
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    ABSTRACT: Beta cell injury due to oxidative stress is a typical etiology of diabetes caused by nutritional excess, but its precise mechanism remains largely elusive. Here, we demonstrate that the microtubule motor KIF12 mediates an antioxidant cascade in beta cells as an intracellular target of excess fat intake or "lipotoxicity." KIF12 knockout mice suffer from hypoinsulinemic glucose intolerance due to increased beta cell oxidative stress. Using this model, we identified an antioxidant signaling cascade involving KIF12 as a scaffold for the transcription factor Sp1. The stabilization of nascent Sp1 appeared to be essential for proper peroxisomal function by enhancing Hsc70 expression, and the pharmacological induction of Hsc70 expression with teprenone counteracted the oxidative stress. Because KIF12 is transcriptionally downregulated by chronic exposure to fatty acids, this antioxidant cascade involving KIF12 and Hsc70 is proposed to be a critical target of nutritional excess in beta cells in diabetes.
    Developmental Cell 10/2014; 31(2):202-14. DOI:10.1016/j.devcel.2014.08.028 · 9.71 Impact Factor
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    Nobutaka Hirokawa ·

    BMC Genomics 04/2014; 15(Suppl 2):O19. DOI:10.1186/1471-2164-15-S2-O19 · 3.99 Impact Factor
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    Yoshimitsu Kanai · Daliang Wang · Nobutaka Hirokawa ·
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    ABSTRACT: Multifunctional low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) recognizes and internalizes a large number of diverse ligands, including LDL and factor VIII. However, little is known about the regulation of LRP1 endocytosis. Here, we show that a microtubule-based motor protein, KIF13B, in an unexpected and unconventional function, enhances caveolin-dependent endocytosis of LRP1. KIF13B was highly expressed in the liver and was localized on the sinusoidal plasma membrane of hepatocytes. KIF13B knockout (KO) mice showed elevated levels of serum cholesterol and factor VIII, and KO MEFs showed decreased uptake of LDL. Exogenous KIF13B, initially localized on the plasma membrane with caveolae, was translocated to the vesicles in the cytoplasm with LRP1 and caveolin-1. KIF13B bound to hDLG1 and utrophin, which, in turn, bound to LRP1 and caveolae, respectively. These linkages were required for the KIF13B-enhanced endocytosis of LRP1. Thus, we propose that KIF13B, working as a scaffold, recruits LRP1 to caveolae via LRP1-hDLG1-KIF13B-utrophin-caveolae linkage and enhances the endocytosis of LRP1.
    The Journal of Cell Biology 01/2014; 204(3). DOI:10.1083/jcb.201309066 · 9.83 Impact Factor
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    Maya Maor-Nof · Noriko Homma · Calanit Raanan · Aviv Nof · Nobutaka Hirokawa · Avraham Yaron ·
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    ABSTRACT: Extensive axonal pruning and neuronal cell death are critical events for the development of the nervous system. Like neuronal cell death, axonal elimination occurs in discrete steps; however, the regulators of these processes remain mostly elusive. Here, we identify the kinesin superfamily protein 2A (KIF2A) as a key executor of microtubule disassembly and axonal breakdown during axonal pruning. Knockdown of Kif2a, but not other microtubule depolymerization or severing proteins, protects axonal microtubules from disassembly upon trophic deprivation. We further confirmed and extended this result to demonstrate that the entire degeneration process is delayed in neurons from the Kif2a knockout mice. Finally, we show that the Kif2a-null mice exhibit normal sensory axon patterning early during development, but abnormal target hyperinnervation later on, as they compete for limited skin-derived trophic support. Overall, these findings reveal a central regulatory mechanism of axonal pruning during development.
    Cell Reports 04/2013; 3(4). DOI:10.1016/j.celrep.2013.03.005 · 8.36 Impact Factor
  • Shinsuke Niwa · Hironori Takahashi · Nobutaka Hirokawa ·
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    ABSTRACT: Microtubules are fundamental to neuronal morphogenesis and function. Mutations in tubulin, the major constituent of microtubules, result in neuronal diseases. Here, we have analysed β-tubulin mutations that cause neuronal diseases and we have identified mutations that strongly inhibit axonal transport of vesicles and mitochondria. These mutations are in the H12 helix of β-tubulin and change the negative charge on the surface of the microtubule. This surface is the interface between microtubules and kinesin superfamily motor proteins (KIF). The binding of axonal transport KIFs to microtubules is dominant negatively disrupted by these mutations, which alters the localization of KIFs in neurons and inhibits axon elongation in vivo. In humans, these mutations induce broad neurological symptoms, such as loss of axons in the central nervous system and peripheral neuropathy. Thus, our data identified the critical region of β-tubulin required for axonal transport and suggest a molecular mechanism for human neuronal diseases caused by tubulin mutations.
    The EMBO Journal 03/2013; 32(10). DOI:10.1038/emboj.2013.59 · 10.43 Impact Factor
  • Qing Chang · Ryo Nitta · Shigeyuki Inoue · Nobutaka Hirokawa ·
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    ABSTRACT: Kinesin superfamily proteins (KIFs) are microtubule-based molecular motors driven by the energy derived from the hydrolysis of ATP. Previous studies have revealed that the ATP binding step is crucial both for the power stroke to produce motility and for the inter-domain regulation of ATPase activity to guarantee the processive movement of dimeric KIFs. Here, we report the first crystal structure of KIF4 complexed with the non-hydrolyzable ATP analog, AMPPNP (adenylyl imidodiphosphate), at 1.7 Å resolution. By combining our structure with previously solved KIF1A structures complexed with two ATP analogs, molecular snapshots during ATP binding reveal that the closure of the nucleotide-binding pocket during ATP binding is achieved by closure of the backdoor. Closure of the backdoor stabilizes two mobile regions, switch I and switch II, to generate the phosphate tube from which hydrolyzed phosphate is released. Through the stabilization of switch II, the local conformational change at the catalytic center is further relayed to the neck-linker element that fully docks to the catalytic core to produce the power stroke. Because the neck-linker is a sole element that connects the partner heads in dimeric KIFs, this tight structural coordination between the catalytic center and neck-linker enables inter-domain communication between the partner heads. This study also revealed the putative microtubule binding site of KIF4, thus providing structural insights that describe the specific binding of KIF4 to the microtubule. (226 words).
    Journal of Molecular Biology 03/2013; 425(11). DOI:10.1016/j.jmb.2013.03.004 · 4.33 Impact Factor
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    Ruyun Zhou · Shinsuke Niwa · Laurent Guillaud · Ying Tong · Nobutaka Hirokawa ·
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    ABSTRACT: Molecular motors are fundamental to neuronal morphogenesis and function. However, the extent to which molecular motors are involved in higher brain functions remains largely unknown. In this study, we show that mice deficient in the kinesin family motor protein KIF13A (Kif13a(-/-) mice) exhibit elevated anxiety-related behavioral phenotypes, probably because of a reduction in 5HT(1A) receptor (5HT(1A)R) transport. The cell-surface expression level of the 5HT(1A)R was reduced in KIF13A-knockdown neuroblastoma cells and Kif13a(-/-) hippocampal neurons. Biochemical analysis showed that the forkhead-associated (FHA) domain of KIF13A and an intracellular loop of the 5HT(1A)R are the interface between the motor and cargo vesicles. A minimotor consisting of the motor and FHA domains is able to transport 5HT(1A)R-carrying organelles in in vitro reconstitution assays. Collectively, our results suggest a role for this molecular motor in anxiety control.
    Cell Reports 02/2013; 3(2):509-19. DOI:10.1016/j.celrep.2013.01.014 · 8.36 Impact Factor
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    Kazuo Nakajima · Xiling Yin · Yosuke Takei · Dae-Hyun Seog · Noriko Homma · Nobutaka Hirokawa ·
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    ABSTRACT: KIF5 (also known as kinesin-1) family members, consisting of KIF5A, KIF5B, and KIF5C, are microtubule-dependent molecular motors that are important for neuronal function. Among the KIF5s, KIF5A is neuron specific and highly expressed in the central nervous system. However, the specific roles of KIF5A remain unknown. Here, we established conditional Kif5a-knockout mice in which KIF5A protein expression was postnatally suppressed in neurons. Epileptic phenotypes were observed by electroencephalogram abnormalities in knockout mice because of impaired GABA(A) receptor (GABA(A)R)-mediated synaptic transmission. We also identified reduced cell surface expression of GABA(A)R in knockout neurons. Importantly, we identified that KIF5A specifically interacted with GABA(A)R-associated protein (GABARAP) that is known to be involved in GABA(A)R trafficking. KIF5A regulated neuronal surface expression of GABA(A)Rs via an interaction with GABARAP. These results provide an insight into the molecular mechanisms of KIF5A, which regulate inhibitory neural transmission.
    Neuron 12/2012; 76(5):945-961. DOI:10.1016/j.neuron.2012.10.012 · 15.05 Impact Factor
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    ABSTRACT: Cilia control homeostasis of the mammalian body by generating fluid flow. It has long been assumed that ciliary length-control mechanisms are essential for proper flow generation, because fluid flow generation is a function of ciliary length. However, the molecular mechanisms of ciliary length control in mammals remain elusive. Here, we suggest that KIF19A, a member of the kinesin superfamily, regulates ciliary length by depolymerizing microtubules at the tips of cilia. Kif19a(-/-) mice displayed hydrocephalus and female infertility phenotypes due to abnormally elongated cilia that cannot generate proper fluid flow. KIF19A localized to cilia tips, and recombinant KIF19A controlled the length of microtubules polymerized from axonemes in vitro. KIF19A had ATP-dependent microtubule-depolymerizing activity mainly at the plus end of microtubules. Our results indicated a molecular mechanism of ciliary length regulation in mammals, which plays an important role in the maintenance of the mammalian body.
    Developmental Cell 11/2012; 23(6). DOI:10.1016/j.devcel.2012.10.016 · 9.71 Impact Factor
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    Hiroaki Yajima · Toshihiko Ogura · Ryo Nitta · Yasushi Okada · Chikara Sato · Nobutaka Hirokawa ·
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    ABSTRACT: Microtubules are dynamic polymers that stochastically switch between growing and shrinking phases. Microtubule dynamics are regulated by guanosine triphosphate (GTP) hydrolysis by β-tubulin, but the mechanism of this regulation remains elusive because high-resolution microtubule structures have only been revealed for the guanosine diphosphate (GDP) state. In this paper, we solved the cryoelectron microscopy (cryo-EM) structure of microtubule stabilized with a GTP analogue, guanylyl 5'-α,β-methylenediphosphonate (GMPCPP), at 8.8-Å resolution by developing a novel cryo-EM image reconstruction algorithm. In contrast to the crystal structures of GTP-bound tubulin relatives such as γ-tubulin and bacterial tubulins, significant changes were detected between GMPCPP and GDP-taxol microtubules at the contacts between tubulins both along the protofilament and between neighboring protofilaments, contributing to the stability of the microtubule. These findings are consistent with the structural plasticity or lattice model and suggest the structural basis not only for the regulatory mechanism of microtubule dynamics but also for the recognition of the nucleotide state of the microtubule by several microtubule-binding proteins, such as EB1 or kinesin.
    The Journal of Cell Biology 07/2012; 198(3):315-22. DOI:10.1083/jcb.201201161 · 9.83 Impact Factor
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    Xiling Yin · Xue Feng · Yosuke Takei · Nobutaka Hirokawa ·
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    ABSTRACT: Regulation of NMDA receptor trafficking is crucial to modulate neuronal communication. Ca(2+)/calmodulin-dependent protein kinase phosphorylates the tail domain of KIF17, a member of the kinesin superfamily, to control NMDA receptor subunit 2B (GluN2B) transport by changing the KIF17-cargo interaction in vitro. However, the mechanisms of regulation of GluN2B transport in vivo and its physiological significance are unknown. We generated transgenic mice carrying wild-type KIF17 (TgS), or KIF17 with S1029A (TgA) or S1029D (TgD) phosphomimic mutations in kif17(-/-) background. TgA/kif17(-/-) and TgD/kif17(-/-) mice exhibited reductions in synaptic NMDA receptors because of their inability to load/unload GluN2B onto/from KIF17, leading to impaired neuronal plasticity, CREB activation, and spatial memory. Expression of GFP-KIF17 in TgS/kif17(-/-) mouse neurons rescued the synaptic and behavioral defects of kif17(-/-) mice. These results suggest that phosphorylation-based regulation of NMDA receptor transport is critical for learning and memory in vivo.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2012; 32(16):5486-99. DOI:10.1523/JNEUROSCI.0718-12.2012 · 6.34 Impact Factor
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    Makoto Kondo · Yosuke Takei · Nobutaka Hirokawa ·
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    ABSTRACT: Environmental enrichment causes a variety of effects on brain structure and function. Brain-derived neurotrophic factor (BDNF) plays an important role in enrichment-induced neuronal changes; however, the precise mechanism underlying these effects remains uncertain. In this study, a specific upregulation of kinesin superfamily motor protein 1A (KIF1A) was observed in the hippocampi of mice kept in an enriched environment and, in hippocampal neurons in vitro, BDNF increased the levels of KIF1A and of KIF1A-mediated cargo transport. Analysis of Bdnf(+/-) and Kif1a(+/-) mice revealed that a lack of KIF1A upregulation resulted in a loss of enrichment-induced hippocampal synaptogenesis and learning enhancement. Meanwhile, KIF1A overexpression promoted synaptogenesis via the formation of presynaptic boutons. These findings demonstrate that KIF1A is indispensable for BDNF-mediated hippocampal synaptogenesis and learning enhancement induced by enrichment. This is a new molecular motor-mediated presynaptic mechanism underlying experience-dependent neuroplasticity.
    Neuron 02/2012; 73(4):743-57. DOI:10.1016/j.neuron.2011.12.020 · 15.05 Impact Factor
  • Nobutaka Hirokawa · Yosuke Tanaka · Yasushi Okada ·
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    ABSTRACT: The establishment of left-right asymmetry during development of vertebrate embryos depends on leftward flow in the nodal cavity. The flow is produced by the rotational movement of the posteriorly tilted nodal cilia. However, it remains poorly understood how the nodal cilia are tilted posteriorly, and how the directionality of the flow is translated into gene expression patterns in the embryo. Recent studies have identified signaling molecules involved in these processes. First, planar cell polarity signaling has been shown to be involved in the posterior positioning of the basal bodies of nodal cilia, which leads to the posterior tilting of their rotation axes. Second, identification of putative receptors and signaling molecules suggests a link between the signaling molecules delivered by the nodal flow, and downstream signaling in the cells surrounding the nodal cavity and the lateral plate mesoderm.
    Current opinion in cell biology 02/2012; 24(1):31-9. DOI:10.1016/ · 8.47 Impact Factor
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    ABSTRACT: Neuronal morphology is regulated by cytoskeletons. Kinesin superfamily protein 2A (KIF2A) depolymerizes microtubules (MTs) at growth cones and regulates axon pathfinding. The factors controlling KIF2A in neurite development remain totally elusive. Here, using immunoprecipitation with an antibody specific to KIF2A, we identified phosphatidylinositol 4-phosphate 5-kinase alpha (PIPKα) as a candidate membrane protein that regulates the activity of KIF2A. Yeast two-hybrid and biochemical assays demonstrated direct binding between KIF2A and PIPKα. Partial colocalization of the clusters of punctate signals for these two molecules was detected by confocal microscopy and photoactivated localization microscopy. Additionally, the MT-depolymerizing activity of KIF2A was enhanced in the presence of PIPKα in vitro and in vivo. PIPKα suppressed the elongation of axon branches in a KIF2A-dependent manner, suggesting a unique PIPK-mediated mechanism controlling MT dynamics in neuronal development.
    Proceedings of the National Academy of Sciences 01/2012; 109(5):1725-30. DOI:10.1073/pnas.1107808109 · 9.67 Impact Factor

Publication Stats

31k Citations
3,134.71 Total Impact Points


  • 2012-2015
    • King Abdulaziz University
      • Center of Excellence In Genomic Medicine Research
      Djidda, Makkah, Saudi Arabia
  • 1970-2015
    • The University of Tokyo
      • • Faculty & Graduate School of Medicine
      • • School of Medicine
      • • Department of Neurology
      Tōkyō, Japan
  • 2011
    • Tokyo University and Graduate School of Social Welfare
      Edo, Tōkyō, Japan
  • 2004
    • Ludwig-Maximilians-University of Munich
      München, Bavaria, Germany
  • 1992
    • Bunkyo University
      Edo, Tōkyō, Japan
  • 1982-1984
    • Washington University in St. Louis
      • Department of Anatomy and Neurobiology
      San Luis, Missouri, United States
  • 1983
    • Yale University
      New Haven, Connecticut, United States