Title:
Ca2+ -dependent regulation of membrane trafficking controls neuronal growth cone guidance
Takuro Tojima, Ph.D.
Laboratory for Neuronal Growth Mechanisms, RIKEN Brain Science Institute
PRESTO, Japan Science and Technology Agency
Abstract:
The growth cone, a motile amoeboid structure at the tip of elongating neuronal axons, migrates along the correct path to form precise neuronal networks. Asymmetric elevation of cytosolic Ca2+concentration across the growth cone, which is triggered upon the reception of extracellular guidance cues, can mediate both attractive and repulsive growth cone guidance. We previously demonstrated that the polarity of growth cone guidance, with respect to the localization of Ca2+signals, is determined by the source of Ca2+ signals in the following manner: Ca2+ influx that is accompanied by Ca2+ -induced Ca2+ release (CICR) through ryanodine receptors on the endoplasmic reticulum membrane triggers growth cone attraction, whereas Ca2+ influx without CICR favors growth cone repulsion. The occurrence of CICR is regulated counteractively by cAMP and nitric oxide-cGMP pathways. We also showed that membrane trafficking system act downstream of Ca2+ signals as a driving machinery for growth cone guidance: asymmetric clathrin-mediated endocytosis and vesicle-associated membrane protein 2 (VAMP2)-mediated exocytosis drive growth cone repulsion and attraction, respectively. Recently, we identified the signaling pathways that link Ca 2+ signals with clathrin-mediated endocytosis: the Ca2+ /calmodulin-dependent protein phosphatase calcineurin acts downstream of Ca2+ influx to facilitate endocytosis for repulsion, whereas Ca2+ /calmodulin-dependent protein kinase II and cyclin-dependent protein kinase 5 act downstream of CICR to inhibit endocytosis for attraction. Altogether, our results reveal signaling mechanisms underlying localized imbalance of membrane trafficking that drives bidirectional growth cone guidance.
References:
Tojima T, Hines JH, Henley JR, Kamiguchi H. Second messengers and membrane trafficking direct and organize growth cone steering. Nature Reviews Neuroscience 12:191-203, 2011
Tojima T, Itofusa R, Kamiguchi H. Asymmetric clathrin-mediated endocytosis drives repulsive growth cone guidance. Neuron 66:370-377, 2010
Tojima T , Itofusa R, Kamiguchi H. The nitric oxide-cGMP pathway controls the directional polarity of growth cone guidance via modulating cytosolic Ca 2+ signals. Journal of Neuroscience 29:7886-7897, 2009
Tojima T, Akiyama H, Itofusa R, Li Y, Katayama H, Miyawaki A, Kamiguchi H. Attractive axon guidance involves asymmetric membrane transport and exocytosis in the growth cone. Nature Neuroscience 10:58-66, 2007
Ooashi N, Futatsugi A, Yoshihara F, Mikoshiba K, Kamiguchi H. Cell adhesion molecules regulate Ca 2+ -mediated steering of growth cones via cyclic AMP and ryanodine receptor type 3. Journal of Cell Biology 170:1159-1167, 2005
