GSK-3[alpha]/[beta]-mediated phosphorylation of CRMP-2 regulates activity-dependent dendritic growth

• Published in: Journal of neurochemistry 2013-06, Vol.125 (5), p.685
• Main Authors: Tan, Minghui, Ma, Shanshan, Huang, Qiaoying, Hu, Kunhua, Song, Bin, Li, Mingtao
• Format: Article
• Language: English
• Subjects: Brain; Neurons; Phosphorylation
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12230

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)[alpha]/[beta] on Ser21/9 in cerebellar granule neurons. Using several approaches, including gene knockdown and GSK-3[alpha]/[beta]S21A/S21A/S9A/S9A double knockin mice, we demonstrated that both GSK-3[beta] and GSK-3[alpha] mediate activity-dependent dendritic growth and that Ser21/9 phosphorylation of GSK-3[alpha]/[beta] 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. [PUBLICATION ABSTRACT]