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Analyses of Actin Dynamics, Clutch Coupling and Traction Force for Growth Cone Advance
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A CaMKII/calcineurin switch controls the direction of Ca(2+)-dependent growth cone guidance

Zhexing Wen1, Carmine Guirland, Guo-Li Ming

  • 1Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.

Neuron
|September 15, 2004
PubMed

Insights

Calcium signaling directs axon growth cone turning. Calcium-calmodulin-dependent protein kinase II (CaMKII) and calcineurin (CaN) act as a switch, with different calcium levels controlling attraction or repulsion during neural development.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Axon pathfinding is crucial for neural circuit formation.
  • Growth cone turning, guided by extracellular cues, is essential for axon navigation.
  • Localized cytosolic Ca2+ signals mediate bidirectional growth cone responses, but downstream effectors are unclear.

Purpose of the Study:

  • To elucidate the downstream molecular mechanisms controlling Ca2+-dependent growth cone turning.
  • To identify the key signaling molecules that switch between attractive and repulsive guidance.

Main Methods:

  • Investigated the roles of Ca2+-dependent protein kinases and phosphatases in growth cone turning.
  • Manipulated local Ca2+ concentrations and resting intracellular Ca2+ levels.
  • Examined the influence of the cAMP pathway on Ca2+ signaling.

Main Results:

  • Calcium-calmodulin-dependent protein kinase II (CaMKII) and calcineurin (CaN) act as a switch for Ca2+-dependent growth cone turning.
  • High local Ca2+ activates CaMKII for attraction; modest Ca2+ activates CaN/phosphatase-1 (PP1) for repulsion.
  • Resting Ca2+ levels modulate CaMKII/CaN activity, with low baseline favoring repulsion.
  • The cAMP pathway inhibits CaN-PP1 signaling, reducing repulsion.
  • CaMKII/CaN-PP1 signaling mediates netrin-1-induced guidance.

Conclusions:

  • A complex Ca2+ signaling mechanism involving the balance of CaMKII and CaN-PP1 activation controls growth cone turning.
  • This switch-like mechanism allows for precise directional responses to extracellular cues during axon pathfinding.
  • Findings reveal novel insights into the molecular basis of neural development and guidance.

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