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Metallothionein I/II induces growth cone chemotaxis via an LRP­1 and LRP­2 dependent mechanism

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Landowski, LM and Gasperini, RJ and Taylor, BVM and West, AK and Foa, LC, Metallothionein I/II induces growth cone chemotaxis via an LRP 1 and LRP 2 dependent mechanism, Neuroscience 2012, 13-17 October, 2012, New Orleans, Louisiana (2012) [Conference Extract]


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Abstract

Introduction: Axon guidance is essential in the developing nervous system as well as in regeneration and re­innervation of target tissues after neuronal injury. It is likely that both traditional and novel receptor­ligand systems are necessary to guide axon growth cones post nerve injury. We examined a novel guidance cue­receptor mechanism: metallothionein I/II (MTI/II) chemoattraction, mediated via the lipoprotein receptor­related proteins 1 and 2 (LRP­1 and LRP­2).

Methods: The turning response of growth cones from embryonic (E16­18) rat dorsal root ganglia were measured in vitro, using the growth cone turning assay 1 . Immunohistochemistry and western blotting were used to quantify protein levels in control and knockdown cultures.

Results: Immunocytostaining established that LRP­1 and LRP­2 are found at the leading edge and on filopodia, suggesting that they are part of the environment­sensing machinery of growth cones. We tested a range of LRP ligands for chemotactic properties using the growth cone turning assay, including MTI/II, ApoE3, tissue plasminogen activator, alpha­2­ macroglobulin and transthyretin. The only LRP ligands tested that elicited a turning response in growth cones were MTI/II and MTIII. Growth cones were attracted to MTI/II (turning angle 9.8°±1.7°, n=11, p<0.0001, compared to control ­1.8° ± 1.1°). Interestingly, the structurally related MTIII protein induced robust growth cone repulsion (­13.8°±1.9°, n=14, p<0.0001). Growth cone turning towards a gradient of MTI/II was abolished by LRP­receptor inhibition with receptor associated protein (RAP, 0.6°± 1.2) and siRNA knockdown of LRP­1 (3.5° ± 1.9) or LRP­2 (3.6° ± 2.5). This data demonstrates that both LRP­1 and LRP­2 are necessary for MTI/II­mediated chemotactic signal transduction. MTI/IImediated chemotaxis was found to be dependent on calcium ion concentration, removal of extracellular calcium abolished chemoattraction. Furthermore, pharmacological inhibition of calcium/calmodulin­dependent kinase II suggests that LRP1 and LRP2 signal via established downstream effectors. The LRP­MTI/II chemotactic system represents a novel, nonclassical axon guidance system that may be exploited in repairing the injured nervous system.

Item Details

Item Type:Conference Extract
Keywords:regeneration, peripheral nervous system, axon guidance
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Peripheral Nervous System
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Nervous System and Disorders
Author:Landowski, LM (Dr Lila Landowski)
Author:Gasperini, RJ (Dr Rob Gasperini)
Author:Taylor, BVM (Professor Bruce Taylor)
Author:West, AK (Professor Adrian West)
Author:Foa, LC (Associate Professor Lisa Foa)
ID Code:106586
Year Published:2012
Deposited By:Wicking Dementia Research and Education Centre
Deposited On:2016-02-15
Last Modified:2016-02-25
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