Faculty Profiles - KINOSHITA, Makoto

Papers - KINOSHITA, Makoto

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[Diverse physiological functions of the septin system: the protean cytoskeleton]. Invited Reviewed

Makoto Kinoshita

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme Vol. 54 ( 9 ) page： 1150 - 8 2009.7

パーキンソン病関連遺伝子Sept4 Invited Reviewed

猪原匡史、木下　専

「パーキンソン病―基礎・臨床研究のアップデート」日本臨牀 76巻増刊号4（通巻1142号） Vol. 76 ( 4 ) page： 75 - 78 2009.6

[Functions of the septin cytoskeleton and its roles in dopaminergic neurotransmission]. Invited Reviewed

Masafumi Ihara, Makoto Kinoshita

Brain and nerve = Shinkei kenkyu no shinpo Vol. 61 ( 4 ) page： 419 - 28 2009.4

Authorship：Last author,　Corresponding author Language：Japanese Publishing type：Research paper (scientific journal)

Cytoskeletal polymers are component of cellular infrastructure that are required for fundamental biological processes ranging from cell division to brain functions. Unlike the knowledge available for tubulin and actin, our understanding of unconventional cytoskeletal structures composed of GTP-binding proteins belonging to the septin family is limited, despite their ubiquity and implications in human diseases. Recent studies have revealed that septin plays unique modulatory roles as an accessory component of microtubules and the actin cytoskeleton. Morphological analyses of the mammalian brain and neural cells have revealed that septins preferentially cluster beneath the extra-synaptic membrane domains in dendritic shafts and spine necks, presynaptic terminals of major neurons, and astroglial processes. Live imaging analysis revealed that septin polymers are remarkably stable in these clusters, which may serve as local cytoskeleton and/or scaffold for the organization of specialized cortical domains in neurons and glia. This hypothesis has been supported by the hypo-dopaminergic phenotype of mice that lack the Sept4 subunit and the hyper-dopaminergic phenotype of those with excess Sept4. In these cases, the septin scaffold in the dopamine neurons is considered as a determinant of the quantity of a subset of presynaptic molecules, including tSNAREs (membrane-fusion machinery) and the dopamine transporters. This finding in mouse models is in agreement with the recent findings that qualitative and/or quantitative dysregulation of septins is involved in neurodegenerative disorders such as Parkinson disease and psychological disorders such as schizophrenia and bipolar disorder. Studies on tubulin/actin indicate that a better understanding of the septin family of proteins will improve our insight into neuropathological phenomena in neurodegenerative and psychological disorders, which may help develop diagnostic markers and therapeutic strategies for such diseases.

Scopus

PubMed

Other Link： http://orcid.org/0000-0002-7102-4048

Spatiotemporal association of DNAJB13 with the annulus during mouse sperm flagellum development. Reviewed International coauthorship International journal

Jikui Guan, Makoto Kinoshita, Li Yuan

BMC developmental biology Vol. 9 ( 1 ) page： 23 - 23 2009.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science $\mathplus$ Business Media

BACKGROUND: The sperm annulus is a septin-based fibrous ring structure connecting the midpiece and the principal piece of the mammalian sperm flagellum. Although ultrastructural abnormalities and functional importance of the annulus have been addressed in Sept4-null mutant mice and a subset of human patients with asthenospermia syndrome, little is known about how the structure is assembled and positioned to the midpiece-principal piece junction during mammalian sperm flagellum development. RESULTS: By performing immunofluorescence and biochemical approaches with antibodies against DNAJB13 and an annulus constituent SEPT4, we report here a spatiotemporal association of DNAJB13 with sperm annulus during mouse sperm flagellum development. DNAJB13 co-localized with SEPT4 to the annulus, and both were first able to be detected in step 9 spermatids. As spermiogenesis proceeded, the annular DNAJB13 immunosignal increased until the annulus reached the midpiece-principal piece junction, and then gradually disappeared from it in late spermiogenesis. In contrast, the SEPT4 immunosignal was relatively unaltered, and still present on annulus of mature spermatozoa. In Sept4-null mouse spermatids lacking the annulus structure, the annulus-like DNAJB13 immunosignal was still able to be detected, albeit weaker, at the neck region of the flagella. In vitro DNAJB13 was co-localized and interacted with SEPT4 directly. CONCLUSION: The direct interaction of DNAJB13 with SEPT4 in vitro and its spatiotemporal association with the annulus during sperm flagellum development, and even its annulus-like appearance in the annulus-deficient spermatids, suggest that DNAJB13 may be involved in assembling the annulus structure and positioning it towards the midpiece-principal piece junction.

DOI： 10.1186/1471-213X-9-23

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Septin-Mediated Uniform Bracing of Phospholipid Membranes Reviewed

Yohko Tanaka-Takiguchi, Makato Kinoshita, Kingo Takiguchi

Current Biology Vol. 19 ( 2 ) page： 140 - 145 2009.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier {BV}

Cell shape is determined by the interplay between the lipid bilayer and the underlying network of protein polymers [1]. We explored unknown determinants involved in cell morphogenesis as factors that transform phospholipid-based liposomes (diameter 5-20 mu m). Unlabeled giant liposomes, observed through dark-field optics, were metastable in an aqueous suspension. In contrast, liposomes robustly protruded uniform tubules immediately after the addition of a brain extract to the suspension. The tubulation reaction was greatly facilitated when the liposomes contained PIP or PIP2. Biochemical analysis of the brain extract revealed that heteromeric complexes of septins, a family of polymerizing GTP/GDP-binding proteins, are responsible for the membrane transformation. Ultrastructural analysis established that each membrane tubule (diameter 0.43 +/- 0.079 mu m) is braced by a circumferential array of septin filaments. Although submembranous septin assemblies are associated with diverse cortical morphogenesis from yeast to mammals [2-5], the biophysical basis for the septin-membrane interplay remains largely unknown. Further, there is a biochemical discrepancy between the fast septin remodeling in cells and their slow self-assembly in vitro [6, 7]. This membrane-facilitated fast septin assembly demonstrated for the first time by our unique experimental system should provide important clues to characterize these processes.

DOI： 10.1016/j.cub.2008.12.030

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Amoeboid T lymphocytes require the septin cytoskeleton for cortical integrity and persistent motility. Reviewed International coauthorship International journal

Aaron J Tooley, Julia Gilden, Jordan Jacobelli, Peter Beemiller, William S Trimble, Makoto Kinoshita, Matthew F Krummel

Nature Cell Biology Vol. 11 ( 1 ) page： 17 - 26 2009.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Nature Publishing Group

The systems that refine actomyosin forces during motility remain poorly understood. Septins assemble on the T-cell cortex and are enriched at the mid-zone in filaments. Septin knockdown causes membrane blebbing, excess leading-edge protrusions and lengthening of the trailing-edge uropod. The associated loss of rigidity permits motility, but cells become uncoordinated and poorly persistent. This also relieves a previously unrecognized restriction to migration through small pores. Pharmacologically rigidifying cells counteracts this effect, and relieving cytoskeletal rigidity synergizes with septin depletion. These data suggest that septins tune actomyosin forces during motility and probably regulate lymphocyte trafficking in confined tissues.

DOI： 10.1038/ncb1808

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Sept4 Invited

祝迫惠子、木下　専

分子細胞治療 (先端医学社) Vol. 8 ( 2 ) page： 68 - 69 2009

物質輸送システムの支持機構としてのセプチン系とその破綻 Invited Reviewed

木下　専

創薬研究者必見!最新トランスポーター研究2009 (遺伝子医学MOOK) page： 95 - 101 2009

Septins as diagnostic markers for a subset of human asthenozoospermia. Reviewed International journal

Yoshio Sugino, Kentaro Ichioka, Takeshi Soda, Masafumi Ihara, Makoto Kinoshita, Osamu Ogawa, Hiroyuki Nishiyama

The Journal of Urology Vol. 180 ( 6 ) page： 2706 - 2709 2008.12

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier {BV}

PURPOSE: Septins are the major constituents of the annulus, a submembranous ring that separates the middle and principal pieces of spermatozoa. We previously reported its essential role in spermiogenesis and reproduction in mice. In the current study we investigated septin abnormality in infertile men. MATERIALS AND METHODS: Semen samples from 108 infertile patients and 21 healthy volunteers were analyzed for sperm concentration and motility. Spermatozoa were immunostained for the 2 representative septin subunits SEPT4 and SEPT7. Peripheral blood DNA from 8 patients with asthenozoospermia who had defective SEPT4 and/or SEPT7 labeling in the annuli was analyzed by direct sequencing. Clinical information and a followup review of pregnancy were obtained retrospectively from medical records. RESULTS: Specific antibodies for SEPT4 and SEPT7 consistently labeled the annuli in spermatozoa from the 21 healthy volunteers, while 14 of 108 samples (13%) from infertile patients showed defective labeling. In 33 patients with asthenozoospermia 10 samples (30%) demonstrated defective labeling for SEPT4 and/or SEPT7. We could not detect exon mutations in the SEPT4 gene by sequencing peripheral blood DNA from 8 patients with asthenozoospermia who had defective SEPT4 and/or SEPT7 labeling. During followup 8 of 14 patients (57%) with SEPT4 and/or SEPT7 labeling defects achieved successful pregnancies. CONCLUSIONS: Annulus defects were found exclusively in infertile patients. Although their prognoses do not differ from those without annulus defects, annulus labeling by septin antibodies may serve as an index for classifying a subset of spermatogenesis defects and monitoring sperm quality.

DOI： 10.1016/j.juro.2008.08.005

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Loss of Sept4 exacerbates liver fibrosis through the dysregulation of hepatic stellate cells Reviewed

Keiko Iwaisako, Etsuro Hatano, Kojiro Taura, Akio Nakajima, Masaharu Tada, Satoru Seo, Nobuyuki Tamaki, Fumiaki Sato, Iwao Ikai, Shinji Uemoto, Makoto Kinoshita

Journal of Hepatology Vol. 49 ( 5 ) page： 768 - 778 2008.11

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier {BV}

Background/Aims: Septins are ubiquitous and multifunctional scaffold proteins involved in cytoskeletal organization, exocytosis and other cellular processes. We disclose the quiescent hepatic stellate cells (HSCs)-specific expression of a septin subunit Sept4 in the liver, and explore the significance of the septin system in liver fibrosis.
Methods: We analyzed the expression of alpha-smooth muscle actin (alpha-SMA), collagens and other markers in primary cultured HSCs derived from wild-type and Sept4(-/-) mice. We compared susceptibility of these mice to liver fibrosis induced by either carbon tetrachloride treatment, bile duct ligation or methionine/choline-deficient diet. Collagen deposition, the principal parameter of liver fibrosis, was quantified both histochemically (Masson's trichrome stain) and biochemically (hydroxyproline content).
Results: In vitro, Sept4 mRNA/protein was remarkably downregulated in HSCs through myofibroblastic transformation. Sept4(-/-) HSCs showed normal morphology and proliferation, while myofibroblastic transformation as monitored by the upregulation of alpha-SMA and collagen was accelerated compared to wild-type HSCs. In vivo, liver fibrosis was consistently more severe in Sept4(-/-) mice than in wild-type littermates in all of the three paradigms of hepatitis/liver fibrosis.
Conclusions: These data concordantly indicate that the HSC-specific septin subunit Sept4 and perhaps the septin system are involved in the suppressive modulation of myofibroblastic transformation and fibrogenesis associated with liver diseases. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jhep.2008.05.026

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Structural insights shed light onto septin assemblies and function Invited Reviewed International coauthorship

Yves Barral, Makoto Kinoshita

Current Opinion in Cell Biology Vol. 20 ( 1 ) page： 12 - 18 2008.2

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier {BV}

While the original septin mutants were identified more than 30 years ago for their role in cytokinesis [Hartwell, LH: Genetic control of the cell division cycle in yeast. IV. Genes controlling bud emergence and cytokinesis. Exp Cell Res 1971, 69: 265-276], the architecture of septin complexes and higher order structures has remained a mystery up until very recently. Over the last few months a number of converging approaches have suddenly provided a wealth of structural information about the different levels of septin organization. Here, we review these advancements and highlight their functional consequences.

DOI： 10.1016/j.ceb.2007.12.001

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Morphogenesis of polarized epithelia requires Sept2-mediated coupling of vesicle transport to polyglutamylated microtubules. Reviewed International coauthorship

Spiliotis ET, Hunt S, Hu Q, Kinoshita M, Nelson WJ

Journal of Cell Biology Vol. 180 page： 295-303 2008

Parkin deficient mice display motor disfunction and learning and memory impairment Reviewed

Neuroscience Research Vol. 61 page： S136 - S136 2008

Role of Septin Cytoskeleton in Spine Morphogenesis and Dendrite Development in Neurons Reviewed International coauthorship

Tomoko Tada, Alyson Simonetta, Matthew Batterton, Makoto Kinoshita, Dieter Edbauer, Morgan Sheng

Current Biology Vol. 17 ( 20 ) page： 1752 - 1758 2007.10

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier {BV}

Septins are GTP-binding proteins that polymerize into heteromeric filaments and form microscopic bundles or ring structures in vitro and in vivo. Because of these properties and their ability to associate with membrane, F-actin, and microtubules, septins have been generally regarded as cytoskeletal components [1, 2]. Septins are known to play roles in cytokinesis, in membrane trafficking, and as structural scaffolds; however, their function in neurons is poorly understood. Many members of the septin family, including Septin 7 (Sept7), were found by mass-spectrometry analysis of postsynaptic density (PSD) fractions of the brain [3, 4], suggesting a possible postsynaptic function of septins in neurons. We report that Sept7 is localized at the base of dendritic protrusions and at dendritic branch points in cultured hippocampal neurons-a distribution reminiscent of septin localization in the bud neck of budding yeast. Overexpression of Sept7 increased dendrite branching and the density of dendritic protrusions, whereas RNA interference (RNAi)-mediated knockdown of Sept7 led to reduced dendrite arborization and a greater proportion of immature protrusions. These data suggest that Sept7 is critical for spine morphogenesis and dendrite development during neuronal maturation.

DOI： 10.1016/j.cub.2007.09.039

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Connecting the dots between septins and the DNA damage checkpoint Invited Reviewed

Makoto Kinoshita, Shunichi Takeda

Cell Vol. 130 ( 5 ) page： 777 - 779 2007.9

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：CELL PRESS

In budding yeast, septins are involved in the morphogenesis checkpoint and the DNA damage checkpoint, both of which regulate cell-cycle progression. In this issue of Cell, Kremer et al. (2007) link septins to DNA damage in mammalian cells by identifying a new signaling pathway that includes the adaptors SOCS7 and NCK. As NCK controls actin dynamics, this pathway may connect DNA damage responses and cellular morphology in metazoans.

DOI： 10.1016/j.cell.2007.08.022

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パーキンソン病の病態に迫る Invited

猪原匡史、木下　専

化学と生物 (日本農芸化学会誌) Vol. 45 ( 9 ) page： 598 - 599 2007.9

Phosphorylation of adult type Sept5 (CDCrel-1) by cyclin-dependent kinase 5 inhibits interaction with syntaxin-1 Reviewed

Makoto Taniguchi, Masato Taoka, Makoto Itakura, Akiko Asada, Taro Saito, Makoto Kinoshita, Masami Takahashi, Toshiaki Isobe, Shin-ichi Hisanaga

Journal of Biological Chemistry Vol. 282 ( 11 ) page： 7869 - 7876 2007.3

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Increasing evidence implicates cyclin-dependent kinase 5 (Cdk5) in neuronal synaptic function. We searched for Cdk5 substrates in synaptosomal fractions prepared from mouse brains. Mass spectrometric analysis after two-dimensional SDS-PAGE identified several synaptic proteins phosphorylated by Cdk5-p35; one protein identified was Sept5 (CDCrel-1). Although septins were isolated originally as cell division-related proteins in yeast, Sept5 is expressed predominantly in neurons and is implicated in exocytosis. We confirmed that Sept5 is phosphorylated by Cdk5p35 in vitro and identified Ser(17) of adult type Sept5 (Sept5_v1) as a major phosphorylation site. We found that Ser17 of Sept5_v1 is phosphorylated in mouse brains. Coimmunoprecipitation from synaptosomal fractions and glutathione S-transferase-syntaxin-1A pulldown assays of Sept5_v1 expressed in COS-7 cells showed that phosphorylation of Sept5_v1 by Cdk5-p35 decreases the binding to syntaxin-1. These results indicate that the interaction of Sept5 with syntaxin-1 is regulated by the phosphorylation of Sept_v1 at Ser(17) by Cdk5-p35.

DOI： 10.1074/jbc.M609457200

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Sept4, a Component of Presynaptic Scaffold and Lewy Bodies, Is Required for the Suppression of α-Synuclein Neurotoxicity Reviewed

Masafumi Ihara, Nobuyuki Yamasaki, Akari Hagiwara, Ai Tanigaki, Ayumi Kitano, Rie Hikawa, Hidekazu Tomimoto, Makoto Noda, Masashi Takanashi, Hideo Mori, Nobutaka Hattori, Tsuyoshi Miyakawa, Makoto Kinoshita

Neuron Vol. 53 ( 4 ) page： 519 - 533 2007.2

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier {BV}

In Parkinson disease (PID), alpha-synuclein aggregates called Lewy bodies often involve and sequester Septin4 (Sept4), a polymerizing scaffold protein. However, the pathophysiological significance of this phenomenon is unclear. Here, we show the physiological association of Sept4 with alpha-synuclein, the dopamine transporter, and other presynaptic proteins in dopaminergic neurons; mice lacking Sept4 exhibit diminished dopaminergic neurotransmission due to scarcity of these presynaptic proteins. These data demonstrate an important role for septin scaffolds in the brain. In transgenic mice that express human alpha-synuclein(A53T) (a mutant protein responsible for familial PD), loss of Sept4 significantly enhances neuropathology and locomotor deterioration. In this PID model, insoluble deposits of Ser(129)-phosphorylated alpha-synuclein(A53T) are negatively correlated with the dosage of Sept4. In vitro, direct association with Sept4 protects alpha-synuclein against self-aggregation and Ser(129) phosphorylation. Taken together, these data show that Sept4 may be involved in PID as a dual susceptibility factor, as its insufficiency can diminish dopaminergic neurotransmission and enhance alpha-synuclein neurotoxicity.

DOI： 10.1016/j.neuron.2007.01.019

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蛍光偏光顕微鏡が解いたセプチン線維配向の謎 Invited Reviewed

木下　専

蛋白質核酸酵素 Vol. 52 ( 1 ) 2007.1

Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen Invited

Kinoshita, M., Watanabe, N.

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme Vol. 52 ( 13 Suppl ) page： 1796 - 1799 2007

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Papers - KINOSHITA, Makoto