Essential Roles for GSK-3s and GSK-3-Primed Substrates in Neurotrophin-Induced and Hippocampal Axon Growth

Woo Yang Kim, Feng Quan Zhou, Jiang Zhou, Yukako Yokota, Yan Min Wang, Takeshi Yoshimura, Kozo Kaibuchi, James R R. Woodgett, E. S. Anton, William D D. Snider

Research output: Contribution to journalArticle

179 Citations (Scopus)

Abstract

Glycogen synthase kinase-3β (GSK-3β) 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-3β null mice. We therefore designed an shRNA that targeted both GSK-3 isoforms. Strong knockdown of both GSK-3α and β 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.

Original languageEnglish
Pages (from-to)981-996
Number of pages16
JournalNeuron
Volume52
Issue number6
DOIs
Publication statusPublished - 21-12-2006

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'Essential Roles for GSK-3s and GSK-3-Primed Substrates in Neurotrophin-Induced and Hippocampal Axon Growth'. Together they form a unique fingerprint.

Cite this