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Axonal/Dendritic Growth and Circuit Formation

開催日 2014/9/13
時間 11:00 - 12:00
会場 Poster / Exhibition(Event Hall B)

Localized imbalance between exocytosis and endocytosis steers neuronal growth cones

  • P3-061
  • 糸総 るり香 / Rurika Itofusa:1 戸島 拓郎 / Takuro Tojima:1,2 上口 裕之 / Hiroyuki Kamiguchi:1 
  • 1:理化学研究所脳科学総合研究センター / Lab. for Neuronal Growth Mechanisms, RIKEN BSI, Saitama, Japan 2:科学技術振興機構さきがけ / PRESTO, Japan Science and Technology Agency, Saitama, Japan 

During neuronal network formation, extracellular axon guidance cues guide migrating growth cones along specific routes. Such processes rely on asymmetric elevation of cytosolic Ca2+ concentrations across the growth cone that mediates its bidirectional turning responses to the cues. Downstream of these Ca2+ signals, membrane trafficking can act as a driving machinery for growth cone guidance: localized activation of vesicle-associated membrane protein 2 (VAMP2)-mediated exocytosis or clathrin-mediated endocytosis causes growth cone attraction or repulsion, respectively. However, it remains unclear how Ca2+ can differentially regulate these opposite membrane trafficking events. Here we show that the directional polarity of growth cone steering depends on localized imbalance between exocytosis and endocytosis, and identify Ca2+-dependent signaling pathways mediating such imbalance. In embryonic chicken dorsal root ganglion neurons, repulsive Ca2+ signals promote clathrin-mediated endocytosis through the Ca2+/calmodulin-dependent protein phosphatase calcineurin and 90-kD splice variant of phosphatidylinositol-4-phosphate 5-kinase type-1γ (PIPKIγ90). By contrast, attractive Ca2+ signals facilitate exocytosis but suppress endocytosis via Ca2+/calmodulin-dependent protein kinase II (CaMKII) and cyclin-dependent kinase 5 (Cdk5) that can inactivate PIPKIγ90. Blocking of CaMKII or Cdk5 activities leads to balanced activation of both exocytosis and endocytosis, causing straight growth cone migration even in the presence of guidance signals. Experimental perturbation of the balanced activity in membrane trafficking restores the growth cone's turning response. Remarkably, the direction of this resumed turning depends on relative activities of exocytosis and endocytosis but not on the type of guidance signals. Taken together, our results suggest strongly that growth cone navigation can be redirected by shifting the imbalance between exocytosis and endocytosis, highlighting the importance of membrane trafficking imbalance for axon guidance.

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