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日本-中国神経科学学会合同シンポジウム:Neuronal signaling for development and plasticity
Joint Symposium of the Japan Neuroscience Society and the Chinese Society for Neuroscience:Neuronal signaling for development and plasticity

開催日 2014/9/12
時間 17:10 - 19:10
会場 Room C(502)
Chairperson(s) 上口 裕之 / Hiroyuki Kamiguchi (理研BSI神経成長機構 / RIKEN Brain Science Institute, Japan)

Molecular mechanisms for axon guidance: from Ca2+ signals to membrane trafficking

  • S2-C-3-3
  • 和田 文孝 / Fumitaka Wada:1 上口 裕之 / Hiroyuki Kamiguchi:1 
  • 1:理研BSI神経成長機構 / Lab for Neuronal Growth Mechanisms, RIKEN BSI, Saitama, Japan 

The formation of axon tracts depends on the spatial accuracy of growth cone navigation. Extracellular guidance cues attract or repel an axon via asymmetric elevation of cytosolic Ca2+ concentrations across the growth cone that mediates its attractive or repulsive turning toward or away from the side with Ca2+ elevation, respectively. The distinction between attractive and repulsive Ca2+ signals resides in their source: Ca2+ release from the endoplasmic reticulum (ER) for attraction and Ca2+ influx from the extracellular space for repulsion. Downstream of these Ca2+ signals, local activation of membrane trafficking steers the growth cone bidirectionally, with exocytosis driving attraction and endocytosis causing repulsion. However, it remains unknown how growth cones can discriminate these Ca2+ signals to operate opposite trafficking events. Here we have conducted a large-scale search for Ca2+ effectors that associate with two types of ER Ca2+ channels, ryanodine receptors (RyR) or IP3 receptors (IP3R), and identified myosin Va (MyoVa) as a critical effector for attractive guidance. We have accumulated evidence that MyoVa can respond specifically to ER-derived Ca2+ and trigger exocytic vesicle transport for attraction. First, MyoVa dissociates from RyR in response to high Ca2+, suggesting that MyoVa can detect Ca2+ microdomains on the ER. Second, MyoVa binding to ER Ca2+ channels is a prerequisite for Ca2+-triggered exocytic vesicle transport and growth cone attraction. Third, forced dissociation of MyoVa from ER Ca2+ channels using photoactivatable peptides can mimic attractive Ca2+ signals and elicit exocytosis. Importantly, this manipulation on one side of the growth cone is sufficient to initiate attractive turning. Finally, MyoVa binding to ER Ca2+ channels participates in axon guidance in vivo. Thus, we have discovered a novel mechanism for sensing ER-derived Ca2+, highlighting the functional significance of spatial confinement of Ca2+ signals in controlling the polarity of cell migration.

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