title: GSK-3α/β-mediated phosphorylation of CRMP-2 regulates activity-dependent dendritic growth.
abstract: Neuronal activity shapes the dendritic arbour; however, most of the molecular players in this process remain to be identified. We observed that depolarization-induced neuronal activity causes an increase in the phosphorylation of glycogen synthase kinase-3 (GSK-3)α/β on Ser21/9 in cerebellar granule neurons. Using several approaches, including gene knockdown and GSK-3α/β(S21A/S21A/S9A/S9A) double knockin mice, we demonstrated that both GSK-3β and GSK-3α mediate activity-dependent dendritic growth and that Ser21/9 phosphorylation of GSK-3α/β plays an important role in this process. Collapsin response mediator protein-2 (CRMP-2), which is crucial for axon development, is phosphorylated at Thr514 and inactivated by GSK-3. We found CRMP-2 was located mainly in the dendrites of cerebellar granule neurons, in contrast to the axonal distribution in hippocampal neurons. Over-expression of CRMP-2 promoted and knockdown of CRMP-2 impaired dendritic growth, suggesting that CRMP-2 is necessary and sufficient for activity-dependent dendritic development. Furthermore, silencing CRMP-2 completely blocked the dendritic growth-promoting effects of GSK-3 knockdown, and expression of Thr514 nonphosphorylated form of CRMP-2 counteracted the inhibitory effect of constitutively active GSK-3. This data indicate that CRMP-2 functions downstream of GSK-3. Together, these findings identify a novel GSK-3/CRMP-2 pathway that connects neuronal activity to dendritic growth.
authors.affiliation: Department of Pharmacology and the Proteomics Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Minghui
authors.initials: M
authors.lastname: Tan
authors.forename: Shanshan
authors.initials: S
authors.lastname: Ma
authors.forename: Qiaoying
authors.initials: Q
authors.lastname: Huang
authors.forename: Kunhua
authors.initials: K
authors.lastname: Hu
authors.forename: Bin
authors.initials: B
authors.lastname: Song
authors.forename: Mingtao
authors.initials: M
authors.lastname: Li
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003712:Dendrites / Q000502:physiology*; D055879:Gene Knock-In Techniques; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C095114:collapsin response mediator protein-2; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha