Axon-Dendrite Balance

Abstract

Neurons are polarized cells with axons (the site of signal output) and dendrites (the sites of signal input). Not only are these functionally different parts of the cell, but the morphology of axons and dendrites is very different as well. Two groups report that glycogen synthase kinase 3β (GSK-3β) is at the center of a process that regulates the balance of axons and dendrites. Jiang et al. and Yoshimura et al. reported that when GSK-3β activity was increased by transfection of isolated embryonic hippocampal neurons with a constitutively active mutant, the number of cells that formed an axon or extended neurite was decreased, and when GSK-3β activity was inhibited, using multiple methods, the number of cells producing multiple axons increased. The overall number of neurites was unchanged. Inhibition of GSK-3β activity in cultured neurons before or after polarity had been established produced an increase in the number of cells with multiple axons, suggesting a role for GSK-3β in both establishing polarity and maintaining polarity. Jiang et al. identified the phosphatidylinositol 3-kinase (PI3K) pathway as a stimulator of GSK-3β phosphorylation, which inhibits GSK-3β activity. Activation of the PI3K pathway by expression of a constitutively active form of the kinase Akt or inactivation of the phosphatase PTEN by silencing RNA (siRNA) also produced multi-axon neurons. Whereas Jiang et al. explored the processes upstream of GSK-3β, Yoshimura et al. explored the processes downstream of GSK-3β in neuronal polarity. They show that GSK-3β phosphorylated collapsin response mediator protein 2 (CRMP-2) in transfected cells and in vitro. CRMP-2 is known to contribute to axon formation. Treatment of neurons with neurotrophin 3 (NT-3) or brain-derived neurotrophic factor (BDNF) stimulated axon growth and decreased CRMP-2 phosphorylation. Furthermore, the stimulation in axon length was blocked if CRMP-2 abundance was decreased by siRNA. Thus, a pathway involving PI3K regulates the activity of GSK-3β and phosphorylation of the microtubule assembly regulatory protein CRMP-2 to control axon formation and growth in neurons. H. Jiang, W. Guo, X. Liang, Y. Rao, Both the establishment and the maintenance of neuronal polarity require active mechanisms: Critical roles of GSK-3β and its upstream regulators. Cell 120 , 123-125 (2005). [PubMed] T. Yoshimura, Y. Kawano, N. Arimura, S. Kawabata, A. Kikuchi, K. Kaibuchi, GSK-3β regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120 , 137-149 (2005). [PubMed]