KINDAI UNIVERSITY


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KOMADA Munekazu

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FacultyDepartment of Life Science
PositionLecturer
DegreePh.D in Medicine
Commentator Guidehttps://www.kindai.ac.jp/meikan/2315-komada-munekazu.html
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Last Updated :2020/06/01

Education and Career

Academic & Professional Experience

  •   2020 04 ,  - 現在, Lecturer, Faculty of Science and Engnieering, Life Science, Kindai University

Research Activities

Published Papers

  • Bisphenol A exposure induces increased microglia and microglial related factors in the murine embryonic dorsal telencephalon and hypothalamus., Takahashi M, Komada M, Miyazawa K, Goto S, Ikeda Y, Toxicology letters, Toxicology letters, 284, 113 - 119, Mar. 2018 , Refereed
  • Involvement of SF-1 in neurogenesis and neuronal migration in the developing neocortex., Komada M, Takahashi M, Ikeda Y, Neuroscience letters, Neuroscience letters, 600, 85 - 90, Jul. 2015 , Refereed
  • DBZ regulates cortical cell positioning and neurite development by sustaining the anterograde transport of Lis1 and DISC1 through control of Ndel1 dual-phosphorylation., Okamoto M, Iguchi T, Hattori T, Matsuzaki S, Koyama Y, Taniguchi M, Komada M, Xie MJ, Yagi H, Shimizu S, Konishi Y, Omi M, Yoshimi T, Tachibana T, Fujieda S, Katayama T, Ito A, Hirotsune S, Tohyama M, Sato M, The Journal of neuroscience : the official journal of the Society for Neuroscience, The Journal of neuroscience : the official journal of the Society for Neuroscience, 35(7), 2942 - 2958, Feb. 2015 , Refereed
  • WAVE2-Abi2 complex controls growth cone activity and regulates the multipolar-bipolar transition as well as the initiation of glia-guided migration., Xie MJ, Yagi H, Kuroda K, Wang CC, Komada M, Zhao H, Sakakibara A, Miyata T, Nagata K, Oka Y, Iguchi T, Sato M, Cerebral cortex (New York, N.Y. : 1991), Cerebral cortex (New York, N.Y. : 1991), 23(6), 1410 - 1423, Jun. 2013 , Refereed
  • Smoothened controls cyclin D2 expression and regulates the generation of intermediate progenitors in the developing cortex., Komada M, Iguchi T, Takeda T, Ishibashi M, Sato M, Neuroscience letters, Neuroscience letters, 547, 87 - 91, Jun. 2013 , Refereed
  • Elevated plus maze for mice., Komada M, Takao K, Miyakawa T, Journal of visualized experiments : JoVE, Journal of visualized experiments : JoVE, (22), Dec. 02 2008 , Refereed
  • Hedgehog signaling is involved in development of the neocortex., Komada M, Saitsu H, Kinboshi M, Miura T, Shiota K, Ishibashi M, Development (Cambridge, England), Development (Cambridge, England), 135(16), 2717 - 2727, Aug. 2008 , Refereed
  • Expression of Fgf15 is regulated by both activator and repressor forms of Gli2 in vitro., Komada M, Saitsu H, Shiota K, Ishibashi M, Biochemical and biophysical research communications, Biochemical and biophysical research communications, 369(2), 350 - 356, May 02 2008 , Refereed
  • Signaling cascade coordinating growth of dorsal and ventral tissues of the vertebrate brain, with special reference to the involvement of Sonic Hedgehog signaling., Ishibashi M, Saitsu H, Komada M, Shiota K, Anatomical science international / Japanese Association of Anatomists, Anatomical science international / Japanese Association of Anatomists, 80(1), 30 - 36, Mar. 2005 , Refereed
  • Mechanisms underlying neuro-inflammation and neurodevelopmental toxicity in the mouse neocortex following prenatal exposure to ethanol, Munekazu Komada, Nao Hara, Satoko Kawachi, Kota Kawachi, Nao Kagawa, Tetsuji Nagao, Yayoi Ikeda, SCIENTIFIC REPORTS, SCIENTIFIC REPORTS, 7(1), 4934, Jul. 2017 , Refereed
    Summary:Fetal alcohol spectrum disorders (FASD) constitute a wide range of disorders that arise from prenatal exposure to ethanol (EtOH). However, detailed reports regarding the adverse effects of prenatal EtOH exposure on neocortical morphology and its underlying pathogenic mechanisms are limited. In the present study, we aimed to characterize the anatomical abnormalities of neocortical development and their correlation with microglial properties and neuro-inflammation in a mouse model of FASD. We evaluated the development and maturation of the neocortex in ICR mice prenatally exposed to 25% (w/v) EtOH using histological and molecular analyses. Reduced proliferation and excessive cell death were observed in the dorsal telencephalon. Abnormal neuronal distribution, layer formation, and dopaminergic neuronal projections were observed in the neocortex. Disruption of microglial differentiation (M-1/M-2 microglial ratio) and abnormal expression of pro-inflammatory and neurotrophic factors were induced, and these abnormalities were ameliorated by co-treatment with an antiinflammatory drug (pioglitazone). FASD model mice displayed histological abnormalities, microglial abnormalities, and neuro-inflammation in both the embryonic and newborn stages. Thus, antiinflammatory therapeutics may provide a novel preventive approach for the treatment of FASD.
  • Expression of Kisspeptin in Gonadotrope Precursors in the Mouse Pituitary during Embryonic and Postnatal Development and in Adulthood, Yayoi Ikeda, Ayako Tagami, Munekazu Komada, Mifumi Takahashi, NEUROENDOCRINOLOGY, NEUROENDOCRINOLOGY, 105(4), 357 - 371, 2017 , Refereed
    Summary:Background: Kisspeptins are important regulators of the development and function of the hypothalamic-pituitary-gonadal axis. However, the importance of kisspeptin at the pituitary level is unclear. Methods: We examined the expression profile of kisspeptin in the mouse pituitary during development and in adulthood using RT-PCR, quantitative PCR and immunohistochemistry. Results: Kiss1 mRNA was detected in both embryonic and postnatal pituitaries. Kisspeptin- immunoreactive (+) cells were detected from embryonic day (E) 13.5 throughout adulthood, being localized to the rostroventral portion in the anterior pituitary (AP) in embryos, and also to the dorsocaudal AP postnatally. A large proportion of kisspeptin(+) cells were double-labeled with gonadotrope markers including Foxl2, SF-1, and LH beta, and the percentage of LH beta(+) cells in kisspeptin(+) cells increased during development. No kisspeptin(+) cells were positive for the proliferating cell marker MCM7 (minichromosome maintenance protein 7), but a few kisspeptin(+) cells co-expressed the stem/progenitor cell marker Sox2. Kisspeptin expression was similar between sexes and between agonadal SF-1 knockout embryos and wild-type littermates. Kiss1 mRNA levels were not significantly different between sexes or during early postnatal development, but levels in females increased when puberty began and were significantly higher than in males at postpubertal ages. Conclusions: These results suggest that kisspeptin is expressed in gonadotrope precursors during gonadotrope differentiation, and that kisspeptin expression begins soon after the initiation of aGSU production and is extinguished soon after the initiation of LH production. Furthermore, pituitary kisspeptin expression may be regulated in a gonad-independent manner during development, but may be associated with gonadotrope function in adulthood. (C) 2016 S. Karger AG, Basel
  • Prenatal exposure to di(2-ethylhexyl) phthalate impairs development of the mouse neocortex, Munekazu Komada, Yuuya Gendai, Nao Kagawa, Tetsuji Nagao, TOXICOLOGY LETTERS, TOXICOLOGY LETTERS, 259, 69 - 79, Sep. 2016 , Refereed
    Summary:Di(2-ethylhexyl) phthalate (DEHP) is currently the most commonly used phthalate for the production of flexible polyvinyl chloride. Phthalates including DEHP have been labeled as potential endocrine disruptors. The effect on the development of the neocortex, however, is unknown. To evaluate the neurodevelopmental effects of prenatal DEHP exposure at 1 and 100 mg/kg/day or 100 and 500 mg/kg/day in fetal and newborn mice, we performed a detailed histologic analysis of the developing dorsal telencephalon and neocortex. The observation of fetuses exposed to DEHP revealed reductions of proliferation and neurogenesis (1 and 100 mg/kg) and an increase in cell death (500 mg/kg). In addition, the newborns prenatally exposed to DEHP showed an abnormal neuronal distribution and a decrease in neurons. These findings suggest that prenatal DEHP exposure induces neurodevelopmental toxicity associated with the neural stem cell niche and corticogenesis. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Extraction of DNA from human embryos after long-term preservation in formalin and Bouin's solutions, Momoko Nagai, Katsura Minegishi, Munekazu Komada, Maiko Tsuchiya, Tomomi Kameda, Shigehito Yamada, CONGENITAL ANOMALIES, CONGENITAL ANOMALIES, 56(3), 112 - 118, May 2016 , Refereed
    Summary:The "Kyoto Collection of Human Embryos" at Kyoto University was begun in 1961. Although morphological analyses of samples in the Kyoto Collection have been performed, these embryos have been considered difficult to genetically analyze because they have been preserved in formalin or Bouin's solution for 20-50 years. Owing to the recent advances in molecular biology, it has become possible to extract DNA from long-term fixed tissues. The purpose of this study was to extract DNA from wet preparations of human embryo samples after long-term preservation in fixing solution. We optimized the DNA extraction protocol to be suitable for tissues that have been damaged by long-term fixation, including DNA-protein crosslinking damage. Diluting Li2CO3 with 70% ethanol effectively removed picric acid from samples fixed in Bouin's solution. Additionally, 20.0mg/mL proteinase was valuable to lyse the long-term fixed samples. The extracted DNA was checked with PCR amplification using several sets of primers and sequence analysis. The PCR products included at least 295- and 838-bp amplicons. These results show that the extracted DNA is applicable for genetic analyses, and indicate that old embryos in the Kyoto Collection should be made available for future studies. The protocol described in this study can successfully extract DNA from old specimens and, with improvements, should be applicable in research aiming to understand the molecular mechanisms of human congenital anomalies.
  • Filamin A interacting protein plays a role in proper positioning of callosal projection neurons in the cortex, Hideshi Yagi, Yuichiro Oka, Munekazu Komada, Min-Jue Xie, Koichi Noguchi, Makoto Sato, NEUROSCIENCE LETTERS, NEUROSCIENCE LETTERS, 612, 18 - 24, Jan. 2016 , Refereed
    Summary:The callosal connections between the two hemispheres of the neocortex are altered in certain psychiatric disorders including schizophrenia. However, how and why the callosal connection is impaired in patients suffering from psychiatric diseases remain unclear. Filamin A interacting protein (FILIP), whose alteration through mutation relates to schizophrenic pathogenesis, binds to actin-binding proteins and controls neurotransmission. Because cortical excitatory neurons, including callosal projection neurons, migrate to the cortical plate during development, with the actin-binding proteins playing crucial roles during migration, we evaluated whether FILIP is involved in the development of the callosal projection neurons by histological analysis of Filip-knockout mice. The positioning of the callosal projection neurons, especially those expressing Plxnd1, in the superficial layer of the cortex is disturbed in these mice, which suggests that FILIP is a key molecule that links callosal projections to the pathogenesis of brain disorders. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
  • Newborn mice exposed prenatally to bisphenol A show hyperactivity and defective neocortical development, Munekazu Komada, Saki Itoh, Kota Kawachi, Nao Kagawa, Yayoi Ikeda, Tetsuji Nagao, TOXICOLOGY, TOXICOLOGY, 323, 51 - 60, Sep. 2014 , Refereed
    Summary:The central nervous system is especially susceptible to toxic insults during development. Prenatal administration of bisphenol A (BPA) induces histologic anomalies in the dorsal telencephalon of the embryo. Whether these anomalies affect the morphogenesis and maturation of neuronal function of the newborn neocortex, however, is unknown. To evaluate the neurodevelopmental and behavioral effects of prenatal BPA exposure at 20 and 200 mu g/kg/day in newborn mice, we performed a detailed histologic analysis of the neocortex and tested for the presence of behavioral abnormalities in newborn mice prenatally exposed to BPA using our newly developed behavioral test. Observations of newborn mice prenatally exposed to BPA revealed abnormal neuronal distribution and layer formation, hypoplasia of layer 6b, and abnormal dopaminergic neuronal projections in the neocortex. Further, the newborn mice exhibited hyperactivity. These findings suggest that prenatal BPA exposure induces neurobehavioral toxicity associated with abnormal dopaminergic neuronal projections, and abnormal corticogenesis and lamination. Histologic and behavioral analyses of newborn mice are considered useful for assessing the neurodevelopmental and behavioral toxicity of chemicals. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
  • Filamin A-interacting protein (FILIP) is a region-specific modulator of myosin 2b and controls spine morphology and NMDA receptor accumulation, Hideshi Yagi, Takashi Nagano, Min-Jue Xie, Hiroshi Ikeda, Kazuki Kuroda, Munekazu Komada, Tokuichi Iguchi, Rahman M. Tariqur, Soichi Morikubo, Koichi Noguchi, Kazuyuki Murase, Masaru Okabe, Makoto Sato, SCIENTIFIC REPORTS, SCIENTIFIC REPORTS, 4, 6353, Sep. 2014 , Refereed
    Summary:Learning and memory depend on morphological and functional changes to neural spines. Non-muscle myosin 2b regulates actin dynamics downstream of long-term potentiation induction. However, the mechanism by which myosin 2b is regulated in the spine has not been fully elucidated. Here, we show that filamin A-interacting protein (FILIP) is involved in the control of neural spine morphology and is limitedly expressed in the brain. FILIP bound near the ATPase domain of non-muscle myosin heavy chain IIb, an essential component of myosin 2b, and modified the function of myosin 2b by interfering with its actin-binding activity. In addition, FILIP altered the subcellular distribution of myosin 2b in spines. Moreover, subunits of the NMDA receptor were differently distributed in FILIP-expressing neurons, and excitation propagation was altered in FILIP-knockout mice. These results indicate that FILIP is a novel, region-specific modulator of myosin 2b.
  • Neurobehavioral evaluation of mouse newborns exposed prenatally to low-dose bisphenol A, Tetsuji Nagao, Kota Kawachi, Nao Kagawa, Munekazu Komada, JOURNAL OF TOXICOLOGICAL SCIENCES, JOURNAL OF TOXICOLOGICAL SCIENCES, 39(2), 231 - 235, Apr. 2014 , Refereed
    Summary:There have been few neurobehavioral toxicology studies on newborn animals. Thus, we developed a mouse newborn behavioral testing method for evaluating the risk of neurotoxicity of environmental toxicants, by means of determining the newborn's motor activity applying the tare function of an analytical balance. Motor activities including crawling, pivoting, righting or tremors of mouse newborns were evaluated. Tremors of newborns of dams exposed to bisphenol A at 2, 20 or 200 mu g/kg/day on days 5 through 18 of gestation were significantly increased when evaluated on postnatal day 1, as well as those of newborns exposed prenatally to diethylstilbestrol at 0.5 mu g/kg/day. We suggest that our developed testing method may provide a useful addition to neurobehavioral assessment in very young rodents exposed to environmental hormone mimics.
  • Newly developed mouse newborn behavioral testing method for evaluating the risk of neurotoxicity of environmental toxicants, Tetsuji Nagao, Nao Kagawa, Munekazu Komada, JOURNAL OF APPLIED TOXICOLOGY, JOURNAL OF APPLIED TOXICOLOGY, 33(12), 1514 - 1519, Dec. 2013 , Refereed
    Summary:Although there have been a vast number of behavioral toxicology studies carried out on adult mice and rats, there have been few neurobehavioral studies utilizing their newborn animals. Thus, we developed a mouse newborn behavioral testing method for evaluating the risk of neurotoxicity of chemicals, by means of determining the newborn's activity using the tare function of an analytical balance. The unstable weighing values resulting from movement of the newborn on the balance recorded by a personal computer every 0.1s, and the total activities of a newborn from the start time of weighing to individual times of evaluation were calculated. In addition, we confirmed the usefulness of our method by determining the activity of mouse newborns with microcephaly induced by prenatal exposure to a neurotoxicant, methylnitrosourea. Copyright (c) 2012 John Wiley & Sons, Ltd.
  • Developmental effects of oral exposure to diethylstilbestrol on mouse placenta, Tetsuji Nagao, Nao Kagawa, Yoshiaki Saito, Munekazu Komada, JOURNAL OF APPLIED TOXICOLOGY, JOURNAL OF APPLIED TOXICOLOGY, 33(11), 1213 - 1221, Nov. 2013 , Refereed
    Summary:Placental growth and function are of biological significance in that placental tissue promotes prenatal life and the maintenance of pregnancy. Exposure to synthetic estrogens causes embryonic mortality and placental growth restriction in mice. The aim of the present study was to examine the effects of diethylstilbestrol (DES) on placenta in mice. DES at 1, 5, 10 or 15 mu g kg(-1) day(-1), or 17-estradiol (E-2) at 50 mu g kg(-1) day(-1), was administered orally to ICR mice on days 4 through to 8 of gestation. Expression of ER, ER, ERR or ERR mRNA in the junctional or labyrinth zone of the placentas on day 13 was assessed using RT-PCR, as well as the embrynic mortality, embryonic and placental weight, histological changes of labyrinth and ultrastructural changes of the trophoblast giant cells (TGCs). Embryo mortalities in the DES 10 and 15 mu g kg(-1) day(-1) groups were markedly increased. No significant changes in embryonic and placental weight were observed in any DES- or E-2-exposed groups. Expression of ER mRNA in the junctional zone with male embryos in the 5 mu g kg(-1) day(-1) group was significantly higher than that in the control, whereas expression was not determined in the 15 mu g kg(-1) day(-1) group. Histological observation revealed that the placentas exposed to DES at 10 mu g kg(-1) day(-1) lacked the developing labyrinth. Ultrastructural observation of the TGCs showed poor rough-surfaced endoplasmic reticulum in the DES 10 mu g kg(-1) day(-1) group. The present data suggest that developmental changes induced by DES may be related to interference with the nutrition and oxygen exchange between mother and embryo or decreased protein synthesis, resulting in a high frequency of embryo mortality. Copyright (c) 2012 John Wiley & Sons, Ltd.
  • Sonic hedgehog signaling coordinates the proliferation and differentiation of neural stem/progenitor cells by regulating cell cycle kinetics during development of the neocortex, Munekazu Komada, CONGENITAL ANOMALIES, CONGENITAL ANOMALIES, 52(2), 72 - 77, Jun. 2012 , Refereed
    Summary:Sonic hedgehog (Shh) acts as a morphogen in normal development of various vertebrate tissues and organs. Shh signaling is essential for patterning and cell-fate specification, particularly in the central nervous system. Shh signaling plays different roles depending on its concentration, area, and timing of exposure. During the development of the neocortex, a low level of Shh is expressed in the neural stem/progenitor cells as well as in mature neurons in the dorsal telencephalon. Shh signaling in neocortex development has been shown to regulate cell cycle kinetics of radial glial cells and intermediate progenitor cells, thereby maintaining the proliferation, survival and differentiation of neurons in the neocortex. During the development of the telencephalon, endogenous Shh signaling is involved in the transition of slow-cycling neural stem cells to fast-cycling neural progenitor cells. It seems that high-level Shh signaling in the ventral telencephalon is essential for ventral specification, while low-level Shh signaling in the dorsal telencephalon plays important roles in the fine-tuning of cell cycle kinetics. The Shh levels and multiple functions of Shh signaling are important for proper corticogenesis in the developing brain. The present paper discusses the roles of Shh signaling in the proliferation and differentiation of neural stem/progenitor cells.
  • Maternal bisphenol A oral dosing relates to the acceleration of neurogenesis in the developing neocortex of mouse fetuses, Munekazu Komada, Yasuko Asai, Mina Morii, Michie Matsuki, Makoto Sato, Tetsuji Nagao, TOXICOLOGY, TOXICOLOGY, 295(1-3), 31 - 38, May 2012 , Refereed
    Summary:Bisphenol A (BPA), an endocrine-disruptor, is widely used in the production of plastics and resins. Human perinatal exposure to this chemical has been proposed to be a potential risk to public health. Animal studies indicate that postnatal exposure to BPA may affect neocortex development in embryos by accelerated neurogenesis and causing neuronal migration defects. The detailed phenotypes and pathogenetic mechanisms, especially with regard to the proliferation and differentiation of neural stem/progenitor cells, however, have not been clarified. C57BL/6J pregnant mice were orally administered BPA at 200 mu g/kg from embryonic day (E) 8.5 to 13.5, and the fetuses were observed histologically at E14.5. To clarify the histological changes, especially in terms of neurogenesis, proliferation and cell cycle, we performed histological analysis using specific markers of neurons/neural stem cells and cell cycle-specific labeling experiments using thymidine-analog substances. Cortical plate was hyperplastic and the number of neural stem/progenitor cells was decreased after the exposure to BPA. In particular, the maternal BPA oral dosing related to the effects on intermediate progenitor cells (IPCs, neural progenitor cells) in the subventricular zone (SVZ) of dorsal telencephalon. Exposure to BPA associated the promotion of the cell cycle exit in radial glial cells (RGCs, neural stem cells) and IPCs, and decreased the proliferation resulting from the prolong cell cycle length of IPCs in the SVZ. Our data show that maternal oral exposure to BPA related to the disruption of the cell cycle in IPCs and the effects of neurogenesis in the developing neocortex. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
  • Prenatal Findings in Congenital Leukemia: A Case Report, Yukiyasu Sato, Yukiko Izumi, Katsura Minegishi, Munekazu Komada, Shigehito Yamada, Kazuyo Kakui, Keiji Tatsumi, Yoshiki Mikami, Hiroshi Fujiwara, Ikuo Konishi, FETAL DIAGNOSIS AND THERAPY, FETAL DIAGNOSIS AND THERAPY, 29(4), 325 - 330, 2011 , Refereed
    Summary:We here describe a case of congenital leukemia that ended in intrauterine fetal demise at 30 weeks of gestation. Acute enlargement of the fetal trunk, elevated pulsatility index of the umbilical artery with concomitant decline of pulsatility index of the middle cerebral artery, pleural effusion, and polyhydramnios preceded the fetal death. Diagnosis of congenital myeloid leukemia was suggested by microscopic examination of the placental tissue, revealing immature myeloid precursors filling the lumina of fetal vessels in the umbilical cord and chorionic villi. Extensive vascular involvement of the placenta by leukemic cells was considered to be a primary cause of the fetal death. Copyright (C) 2011 S. Karger AG, Basel
  • Methylnitrosourea Induces Neural Progenitor Cell Apoptosis and Microcephaly in Mouse Embryos, Munekazu Komada, Fusako Fujiyama, Shigehito Yamada, Kohei Shiota, Tetsuji Nagao, BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY, BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY, 89(3), 213 - 222, Jun. 2010 , Refereed
    Summary:BACKGROUND: Prenatal exposure to methylnitrosourea (MNU), an alkylating agent, induces microcephaly in mice. However, its pathogenetic mechanism has not been clarified, especially that in the development of the cerebral cortex. METHODS: ICR mice were treated with MNU at 10 mg/kg intraperitoneally on day 13.5 or 15.5 of gestation, and the embryos were observed histologically 24 hr after treatment with MNU or at term. To clarify the pathogenesis of microcephaly and histological changes, especially apoptosis, neurogenesis, and neural migration/positioning, we performed histological analysis employing a cell-specific labeling experiment using thymidine-like substances (BrdU, CldU, and IdU) and markers of neurons/neural stem cells. RESULTS: Histological abnormalities of the dorsal telencephalon, and the excessive cell death of proliferative neural progenitor/stem cells were noted in the MNU-treated embryos. The highest frequencies of cell death occurred at 36 hr after MNU treatment, and little or no neurogenesis was observed in the ventricular zone of the dorsal telencephalon. Abnormality of the radial migration was caused by the reduction of radial fibers in the radial glias. Birth-date analysis revealed the abnormal positioning of neurons and aberrant lamination of the cerebral cortex. CONCLUSIONS: Our data suggest that prenatal exposure to MNU induces the excessive cell death of neural precursor/stem cells, and the defective development of the cerebral cortex, resulting in microcephalic abnormalities. Birth Defects Res (Part B) 89:213-222, 2010. (C) 2010 Wiley-Liss,
  • Mice with Altered Myelin Proteolipid Protein Gene Expression Display Cognitive Deficits Accompanied by Abnormal Neuron-Glia Interactions and Decreased Conduction Velocities, Hisataka Tanaka, Jianmei Ma, Kenji F. Tanaka, Keizo Takao, Munekazu Komada, Koichi Tanda, Ayaka Suzuki, Tomoko Ishibashi, Hiroko Baba, Tadashi Isa, Ryuichi Shigemoto, Katsuhiko Ono, Tsuyoshi Miyakawa, Kazuhiro Ikenaka, JOURNAL OF NEUROSCIENCE, JOURNAL OF NEUROSCIENCE, 29(26), 8363 - 8371, Jul. 2009 , Refereed
    Summary:Conduction velocity (CV) of myelinated axons has been shown to be regulated by oligodendrocytes even after myelination has been completed. However, how myelinating oligodendrocytes regulate CV, and what the significance of this regulation is for normal brain function remain unknown. To address these questions, we analyzed a transgenic mouse line harboring extra copies of the myelin proteolipid protein 1 (plp1) gene (plp1(tg/-) mice) at 2 months of age. At this stage, the plp1(tg/-) mice have an unaffected myelin structure with a normally appearing ion channel distribution, but the CV in all axonal tracts tested in the CNS is greatly reduced. We also found decreased axonal diameters and slightly abnormal paranodal structures, both of which can be a cause for the reduced CV. Interestingly the plp1(tg/-) mice showed altered anxiety-like behaviors, reduced prepulse inhibitions, spatial learning deficits and working memory deficit, all of which are schizophrenia-related behaviors. Our results implicate that abnormalities in the neuron-glia interactions at the paranodal junctions can result in reduced CV in the CNS, which then induces behavioral abnormalities related to schizophrenia.
  • The cyst-branch difference in developing chick lung results from a different morphogen diffusion coefficient, Takashi Miura, Dirk Hartmann, Masato Kinboshi, Munekazu Komada, Makoto Ishibashi, Kohei Shiota, MECHANISMS OF DEVELOPMENT, MECHANISMS OF DEVELOPMENT, 126(3-4), 160 - 172, Mar. 2009 , Refereed
    Summary:The developing avian lung is formed mainly by branching morphogenesis, but there is also a unique cystic structure, the air sac, in the ventral region. It has been shown that mesenchymal tissue is responsible for the differential development of a cystic or branched structure, and that the transcription factor Hoxb may be involved in determining this regional difference. We have previously developed two scenarios for branch-cyst transition, both experimentally and theoretically: increased production or increased diffusion of FGF. The aim of the present study was to discover whether one of these scenarios actually operates in the ventral region of the chick lung. We found that the FGF10 level was lower while the diffusion of FGF10 was more rapid in the ventral lung, indicating that the second scenario is more plausible. There are two possibilities as to why the diffusion of FGF10 differs between the two regions: (1) diffusion is facilitated by the looser tissue organisation of the ventral lung mesenchyme; (2) stronger expression of heparan sulphate proteoglycan ( HSPG) in the dorsal lung traps FGF and decreases the effective diffusion coefficient. Mathematical analysis showed that the dorsal-ventral difference in the amount of HSPG is not sufficient to generate the observed difference in pattern, indicating that both extracellular matrix and tissue architecture play a role in this system. These results suggest that the regional cystic-branched difference within the developing chick lung results from a difference in the rate of diffusion of morphogen between the ventral and dorsal regions due to differential levels of HSPG and a different mesenchymal structure. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
  • Embryogenesis of holoprosencephaly, Kohei Shiota, Shigehito Yamada, Munekazu Komada, Makoto Ishibashi, AMERICAN JOURNAL OF MEDICAL GENETICS PART A, AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 143A(24), 3079 - 3087, Dec. 2007 , Refereed
    Summary:Holoprosencephaly (HPE) is a malformation of the human brain caused primarily by incomplete division of the prosencephalon into two halves and is often associated with various facial anomalies. Although HPE is rather rare in newborns (1/10,000-15,000 births), it is frequently encountered in therapeutic abortuses (>1/250). To date, nine gene mutations responsible for human HPE have been identified, but the pathogenetic mechanisms of the craniofacial anomalies in HPE have just begun to be understood. Here, we summarize our studies on human embryos with HPE and discuss the embryogenesis and the underlying molecular mechanisms of HPE malformations under the following headings: pathology, pathogenesis, and critical period of development. (C) 2007 Wiley-Liss, Inc.
  • Sequential developmental changes in holoprosencephalic mouse embryos exposed to ethanol during the gastrulation period, Daisuke Higashiyama, Hirotomo Saitsu, Munekazu Komada, Toshiya Takigawa, Makoto Ishibashi, Kohei Shiota, BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY, BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY, 79(7), 513 - 523, Jul. 2007 , Refereed
    Summary:Background Prenatal exposure to ethanol induces holoprosencephalic malformations in both humans and laboratory animals. However, its teratogenic window for inducing holoprosencephaly is narrow, and the teratogenic mechanism is not well understood. In the present study, we examined the morphological changes in the craniofacial structures of mouse embryos/fetuses at intervals following ethanol treatment and evaluated gene expression patterns in the embryos. Methods: Pregnant C57BL/6J mice were given two doses of ethanol (30 mg/kg in total) on the morning (7:00 and 11:00 AM) of day 7. The fetuses were observed at E10.5 and E15.5 grossly and/or histologically. The expression of Shh and Nkx2.1 gene transcripts was examined at E8.5 by in situ hybridization. Results: Gross and histological abnormalities of the brain and face were found in ethanol-exposed fetuses, and their midline structures were most frequently affected. The midline commissural fibers were often lacking in ethanol-exposed fetuses, even in those cases without external gross malformations. In situ hybridization revealed down-regulation of Shh and Nkx2.1 genes in ethanol-exposed embryos. Conclusions: The results indicate that ethanol may perturb the expression of some developmental genes at a critical stage of embryonic development and induce holoprosencephaly and other midline craniofacial malformations, including histological brain abnormalities.
  • Expression of the mouse fgf15 gene is directly initiated by Sonic hedgehog signaling in the diencephalon and midbrain, H Saitsu, M Komada, M Suzuki, R Nakayama, J Motoyama, K Shiota, M Ishibashi, DEVELOPMENTAL DYNAMICS, DEVELOPMENTAL DYNAMICS, 232(2), 282 - 292, Feb. 2005 , Refereed
    Summary:Sonic hedgehog (Shh) is a secreted molecule that is thought to regulate tissue growth and patterning in vertebrate embryos. Although it has been reported that Gli transcription factors mediate Shh signaling to the nucleus, little is known about developmental target genes of Gli. In the previous genetic study, we showed that Shh is required for Fgt75 expression in the diencephalon and midbrain. Here, we examined whether Fgt75 is a direct target of Shh signaling through Gli. Shh was expressed in the midline cells and Fgt75 in the medial region of the diencephalon/midbrain by the seven-somite stage. The Fgt75 expression domain coincided with that of Gli1 and overlapped with that of Gli2 at this stage. Fgt75 expression in the diencephalon/midbrain was greatly reduced in the seven-somite Shh mutant embryos. Transgenic analysis showed that the 3.6-kb 5'-flanking region of the Fgt75 gene is sufficient for induction of Fgt75 in the medial/ventral diencephalon/midbrain. Luciferase assay showed that the 3.6-kb Fgt75 enhancer/promoter was activated by Gli2. A Gli-binding site was located 1 kb upstream of the transcription start site and was required for expression in the medial/ventral diencephalon/midbrain in transgenic embryos and for activation in luciferase assay. These findings indicate that Fgt75 is directly regulated by Shh signaling through Gli proteins. (C) 2004 Wiley-Liss, Inc.