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The Journal of Neuroscience, December 20, 2006, 26(51):13344-13356; doi:10.1523/JNEUROSCI.4462-06.2006

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Development/Plasticity/Repair
An Essential Role for the Integrin-Linked Kinase–Glycogen Synthase Kinase-3ß Pathway during Dendrite Initiation and Growth

Sibel Naska,^1,2,4 * Katya J. Park,^1,2,6 * Gregory E. Hannigan,¹ Shoukat Dedhar,⁷ Freda D. Miller,^2,3,4,5,6 and David R. Kaplan^1,2,4,6

¹Cancer Research, ²Developmental Biology, and ³Brain and Behavior Programs, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8, Departments of ⁴Medical Genetics and Microbiology and ⁵Physiology and ⁶Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada M5S 1A8, and ⁷British Columbia Cancer Research Centre, University of British Columbia, Vancouver, British Columbia, Canada V5Z 1L3

Correspondence should be addressed to Dr. Freda D. Miller, Developmental Biology Program, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. Email: fredam{at}sickkids.ca

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-3ß (GSK-3ß). 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-3ß, and inhibition of GSK-3ß (either pharmacologically, with dominant-negative GSK-3ß, or by genetic knockdown) caused robust dendrite initiation. GSK-3ß inhibition also caused dendrite initiation in cultured cortical neurons and growth of hippocampal neurons in slice cultures. GSK-3ß functioned downstream of ILK to regulate dendrite formation, because inhibition of GSK-3ß promoted dendrite initiation even when ILK was simultaneously inhibited. Moreover, GSK-3ß 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-3ß led to increased ERK phosphorylation, and inhibition of MEK completely blocked the effects of GSK-3ß inhibition on dendrite initiation and growth. Thus, the ILK–GSK-3ß pathway plays a key role in regulating dendrite formation in developing mammalian neurons.

Key words: sympathetic neurons; neuronal activity; MEK; cortical neurons; hippocampal neurons; neuronal growth; neuronal development; MAP kinase

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Received April 19, 2006; accepted Nov. 16, 2006.

Correspondence should be addressed to Dr. Freda D. Miller, Developmental Biology Program, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. Email: fredam{at}sickkids.ca

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