RT Journal Article
SR Electronic
T1 An Essential Role for the Integrin-Linked Kinase–Glycogen Synthase Kinase-3β Pathway during Dendrite Initiation and Growth
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 13344
OP 13356
DO 10.1523/JNEUROSCI.4462-06.2006
VO 26
IS 51
A1 Sibel Naska
A1 Katya J. Park
A1 Gregory E. Hannigan
A1 Shoukat Dedhar
A1 Freda D. Miller
A1 David R. Kaplan
YR 2006
UL http://www.jneurosci.org/content/26/51/13344.abstract
AB Multiple cues, including growth factors and circuit activity, signal to regulate the initiation and growth of mammalian dendrites. In this study, we have asked how these environmental cues regulate dendrite formation, and in particular, whether dendrite initiation and growth requires integrin-linked kinase (ILK) or its downstream effector, glycogen synthase kinase-3β (GSK-3β). In cultured sympathetic neurons, NGF and neuronal depolarization activated ILK and promoted dendrite initiation and growth, and inhibition of ILK (either pharmacologically, with a dominant-negative form of ILK, or by genetic knockdown) reduced depolarization-induced dendrite formation. In sympathetic neurons, ILK phosphorylated and inhibited GSK-3β, and inhibition of GSK-3β (either pharmacologically, with dominant-negative GSK-3β, or by genetic knockdown) caused robust dendrite initiation. GSK-3β inhibition also caused dendrite initiation in cultured cortical neurons and growth of hippocampal neurons in slice cultures. GSK-3β functioned downstream of ILK to regulate dendrite formation, because inhibition of GSK-3β promoted dendrite initiation even when ILK was simultaneously inhibited. Moreover, GSK-3β promoted dendrite formation in sympathetic neurons by regulating the activity of a key dendrite formation effector, the MAP (microtubule-associated protein) kinase kinase (MEK)–extracellular signal-regulated protein kinase (ERK) pathway. Specifically, inhibition of GSK-3β led to increased ERK phosphorylation, and inhibition of MEK completely blocked the effects of GSK-3β inhibition on dendrite initiation and growth. Thus, the ILK–GSK-3β pathway plays a key role in regulating dendrite formation in developing mammalian neurons.