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ERATO
Exploratory Research for Advanced Technology 
戦略的創造研究推進事業(総括実施型研究)
創造科学犠実推進事業
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MIKOSHIBA Calciosignal Net
Research Director: Dr.Katsuhiko Mikoshiba
(Professor Department of Molecular Neurobiology The Institute of Medical Science The University of Tokyo Group Director Developmental Brain Science Group Brain Science institute The Institute of Physical and Chemial Reserch(RIKEN))

Research Term 1995-2000
 
Outline of Research Results
 The Mikoshiba calciosignal net project sought ways to better understand the roles of calcium and IP3 in cells as well as their mechanisms in order to establish a more complete and accurate view of cell biochemistry, which should eventually lead to useful pharmacological products and cures of various diseases related to malfunctioning cells.

Research Results

Calcium wave formation at the cleavage furrows: The intracellular free calcium in cleavage-stage Xenopus embryos was studied. Cleavage formation was followed by calcium transients that localized to each stage of cleavage furrows and propagated along the furrows as calcium waves, at least until the blastula stage. The velocity of calcium waves implied an intracellular calcium-releasing activity specifically associated with cleavage furrows. Experiments suggest that IP3 receptor-mediated calcium mobilization plays an essential role in this process.

Dorso-ventral axis formation: Evidence has been obtained that blockage of IP3-induced calcium release in the ventral part of the embryo leads to the conversion of the ventral mesoderm to the dorsal mesoderm, thereby generating ectopic dorsal axes. This finding suggests a role for the IP3/calcium signaling pathway as a ventralizing signal in addition to the already known pathway through glycogen synthase kinase 3b.

IP3R1 essential for proper brain function: It has been found that most IP3R1-deficient mice generated by gene targeting die in utero, and born animals have severe ataxia and tonic or tonic-clonic seizures and die by the weaning period. Electroencephalograms have shown that they suffer from epilepsy, indicating that IP3R1 is essential for proper brain function. It was further found that that the IP3-receptor-defficient knocked-out mice could be used as valuable model animals in developing drugs for epilepsy and cerebellar ataxia.

Development of the micro-CALI process: It has been shown using micro-CALI that IP3 receptors could be inactivated. This procedure provided important clues concerning the outgrowth of the neuronal axon. Experiments suggest that calcium-ion release mediated by the IP3 receptor is deeply involved in neuronal network formation during development and during the learning process.

IP3 receptor in cerebellar plasticity: Purkinje neurons injected with the IP3 receptor antibody and that from the IP3 receptor deficient mice showed a blockage of LTD, suggesting the importance of the IP3 receptor in cerebellar plasticity.

Potency of IP3 induced calcium signaling in cell-shape change: The injection of IP3 into fertilized Xenopus eggs induces a transient calcium increase, and a concomitant cell shape change, showing both contraction and swelling, starting at the injection site accompanying rearrangement of cytoskeletal proteins. The result obtained in the project concludes that calcium release from internal store though IP3 receptor plays a crucial role in cell function.

graph1

Xenopus embryo injeted with a function-blocking antiboby against IP3 receptor

graph2

Role for the Ca2+ release in the cell signaling

 

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Exploratory Research for Advanced Technology 
戦略的創造研究推進事業(総括実施型研究)
創造科学技術推進事業 ERATO