TY - JOUR
T1 - A CaMKII/calcineurin switch controls the direction of Ca 2+-dependent growth cone guidance
AU - Wen, Zhexing
AU - Guirland, Carmine
AU - Ming, Guo Li
AU - Zheng, James Q.
N1 - Funding Information:
We would like to thank Dr. Marc Tessier-Lavigne (Genentech) for providing purified netrin-1 proteins; and Dr. Corey Goodman (UC Berkeley) for providing hSema3A construct. We would also like to thank Dr. Janet Alder (University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School) for her helpful comments on the manuscript. This work is supported by grants from the National Science Foundation and the National Institutes of Health (NIH) to J.Q.Z. G.-l.M. is supported by grants from the Rockefeller Brothers Fund, March of Dimes, and NIH.
PY - 2004/9/16
Y1 - 2004/9/16
N2 - Axon pathfinding depends on attractive and repulsive turning of growth cones to extracellular cues. Localized cytosolic Ca2+ signals are known to mediate the bidirectional responses, but downstream mechanisms remain elusive. Here, we report that calcium-calmodulin-dependent protein kinase II (CaMKII) and calcineurin (CaN) phosphatase provide a switch-like mechanism to control the direction of Ca2+-dependent growth cone turning. A relatively large local Ca2+ elevation preferentially activates CaMKII to induce attraction, while a modest local Ca2+ signal predominately acts through CaN and phosphatase-1 (PP1) to produce repulsion. The resting level of intracellular Ca2+ concentrations also affects CaMKII/CaN operation: a normal baseline allows distinct turning responses to different local Ca2+ signals, while a low baseline favors CaN-PP1 activation for repulsion. Moreover, the cAMP pathway negatively regulates CaN-PP1 signaling to inhibit repulsion. Finally, CaMKII/CaN-PP1 also mediates netrin-1 guidance. Together, these findings establish a complex Ca2+ mechanism that targets the balance of CaMKII/CaN-PP1 activation to control distinct growth cone responses.
AB - Axon pathfinding depends on attractive and repulsive turning of growth cones to extracellular cues. Localized cytosolic Ca2+ signals are known to mediate the bidirectional responses, but downstream mechanisms remain elusive. Here, we report that calcium-calmodulin-dependent protein kinase II (CaMKII) and calcineurin (CaN) phosphatase provide a switch-like mechanism to control the direction of Ca2+-dependent growth cone turning. A relatively large local Ca2+ elevation preferentially activates CaMKII to induce attraction, while a modest local Ca2+ signal predominately acts through CaN and phosphatase-1 (PP1) to produce repulsion. The resting level of intracellular Ca2+ concentrations also affects CaMKII/CaN operation: a normal baseline allows distinct turning responses to different local Ca2+ signals, while a low baseline favors CaN-PP1 activation for repulsion. Moreover, the cAMP pathway negatively regulates CaN-PP1 signaling to inhibit repulsion. Finally, CaMKII/CaN-PP1 also mediates netrin-1 guidance. Together, these findings establish a complex Ca2+ mechanism that targets the balance of CaMKII/CaN-PP1 activation to control distinct growth cone responses.
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U2 - 10.1016/j.neuron.2004.08.037
DO - 10.1016/j.neuron.2004.08.037
M3 - Article
C2 - 15363394
AN - SCOPUS:4544337913
SN - 0896-6273
VL - 43
SP - 835
EP - 846
JO - Neuron
JF - Neuron
IS - 6
ER -