Essential Roles for GSK-3s and GSK-3-primed Substrates in Neurotrophin-induced and Hippocampal Axon Growth

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2006 Dec 21

PMID 17178402

Citations 127

Authors

Woo-Yang Kim

Feng-Quan Zhou

Jiang Zhou

Yukako Yokota

Yan-Min Wang

Takeshi Yoshimura

Kozo Kaibuchi

James R Woodgett

E S Anton

William D Snider

Affiliations

Soon will be listed here.

Abstract

Glycogen synthase kinase-3beta (GSK-3beta) is thought to mediate morphological responses to a variety of extracellular signals. Surprisingly, we found no gross morphological deficits in nervous system development in GSK-3beta null mice. We therefore designed an shRNA that targeted both GSK-3 isoforms. Strong knockdown of both GSK-3alpha and beta markedly reduced axon growth in dissociated cultures and slice preparations. We then assessed the role of different GSK-3 substrates in regulating axon morphology. Elimination of activity toward primed substrates only using the GSK-3 R96A mutant was associated with a defect in axon polarity (axon branching) compared to an overall reduction in axon growth induced by a kinase-dead mutant. Consistent with this finding, moderate reduction of GSK-3 activity by pharmacological inhibitors induced axon branching and was associated primarily with effects on primed substrates. Our results suggest that GSK-3 is a downstream convergent point for many axon growth regulatory pathways and that differential regulation of primed versus all GSK-3 substrates is associated with a specific morphological outcome.

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