An essential role for the integrin-linked kinase-glycogen synthase kinase-3 beta pathway during dendrite initiation and growth.
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-3beta (GSK-3beta). 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-3beta, and inhibition of GSK-3beta (either pharmacologically, with dominant-negative GSK-3beta, or by genetic knockdown) caused robust dendrite initiation. GSK-3beta inhibition also caused dendrite initiation in cultured cortical neurons and growth of hippocampal neurons in slice cultures. GSK-3beta functioned downstream of ILK to regulate dendrite formation, because inhibition of GSK-3beta promoted dendrite initiation even when ILK was simultaneously inhibited. Moreover, GSK-3beta 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-3beta led to increased ERK phosphorylation, and inhibition of MEK completely blocked the effects of GSK-3beta inhibition on dendrite initiation and growth. Thus, the ILK-GSK-3beta pathway plays a key role in regulating dendrite formation in developing mammalian neurons.
Naska
Sibel
S
Cancer Research Program, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
Park
Katya J
KJ
Hannigan
Gregory E
GE
Dedhar
Shoukat
S
Miller
Freda D
FD
Kaplan
David R
DR
D000818:Animals; D000831:Animals, Newborn; D049108:Cell Enlargement; D002478:Cells, Cultured; D003712:Dendrites / Q000201:enzymology*; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology / Q000254:growth & development; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D000099200:Scaffold Protein ILK
D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK; C000605508:Gsk3b protein, rat