Asymmetric retraction of growth cone filopodia following focal inactivation of calcineurin.
The neuronal growth cone is thought to be the site of decision making in nerve growth and guidance. One likely mechanism of how the growth cone translates various extracellular cues into directed motility involves rises in intracellular calcium. A variety of physiological cues, such as adhesion molecules and neurotransmitters, increases intracellular calcium, and artificial manipulations of growth cone calcium levels affect growth cone morphology and neurite outgrowth. The molecular events downstream of calcium fluxes are incompletely understood. Here we show that calcineurin, a protein phosphatase enriched in growth cones that is dependent on calcium ions and calmodulin, functions in neurite outgrowth and directed filopodial motility in cultured chick dorsal root ganglia neurons. Cyclosporin A and FK506, inhibitors of calcineurin, delayed neuritogenesis and inhibited neurite extension. Chromophore-assisted laser inactivation of calcineurin in regions of growth cones causes localized filopodial and lamellipodial retraction and influences the direction of subsequent outgrowth. We suggest that a spatial distribution of calcineurin activity within the growth cone can regulate motility and direct outgrowth.
Chang
H Y
HY
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Takei
K
K
Sydor
A M
AM
Born
T
T
Rusnak
F
F
Jay
D G
DG
D000818:Animals; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D002417:Cattle; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002642:Chick Embryo; D016572:Cyclosporine / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D007834:Lasers; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011090:Polyenes / Q000494:pharmacology; D012394:Rosaniline Dyes; D015398:Signal Transduction; D020123:Sirolimus; D016559:Tacrolimus / Q000494:pharmacology
D002148:Calmodulin-Binding Proteins; D011090:Polyenes; D012394:Rosaniline Dyes; C005095:malachite green; D016572:Cyclosporine; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D020123:Sirolimus; D016559:Tacrolimus