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The Journal of Neuroscience, July 6, 2005, 25(27):6350-6361; doi:10.1523/JNEUROSCI.1517-05.2005

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Cellular/Molecular
Constitutively Active Cytoplasmic c-Jun N-Terminal Kinase 1 Is a Dominant Regulator of Dendritic Architecture: Role of Microtubule-Associated Protein 2 as an Effector

Benny Björkblom,¹ Nina Östman,¹ Vesa Hongisto,¹ Vladislav Komarovski,² Jan-Jonas Filén,¹ Tuula A. Nyman,¹ Tuula Kallunki,³ Michael J. Courtney,² and Eleanor T. Coffey¹

¹Turku Centre for Biotechnology, Åbo Akademi and Turku University, BioCity, FIN-20521 Turku, Finland, ²Department of Neurobiology, A. I. Virtanen Institute, University of Kuopio, FIN-70211 Kuopio, Finland, and ³Institute for Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen, Denmark

Normal functioning of the nervous system requires precise regulation of dendritic shape and synaptic connectivity. Here, we report a severe impairment of dendritic structures in the cerebellum and motor cortex of c-Jun N-terminal kinase 1 (JNK1)-deficient mice. Using an unbiased screen for candidate mediators, we identify the dendrite-specific high-molecular-weight microtubule-associated protein 2 (MAP2) as a JNK substrate in the brain. We subsequently show that MAP2 is phosphorylated by JNK in intact cells and that MAP2 proline-rich domain phosphorylation is decreased in JNK1-/- brain. We developed compartment-targeted JNK inhibitors to define whether a functional relationship exists between the physiologically active, cytosolic pool of JNK and dendritic architecture. Using these, we demonstrate that cytosolic, but not nuclear, JNK determines dendritic length and arbor complexity in cultured neurons. Moreover, we confirm that MAP2-dependent process elongation is enhanced after activation of JNK. Using JNK1-/- neurons, we reveal a dominant role for JNK1 over ERK in regulating dendritic arborization, whereas ERK only regulates dendrite shape under conditions in which JNK activity is low (JNK1-/- neurons). These results reveal a novel antagonism between JNK and ERK, potentially providing a mechanism for fine-tuning the dendritic arbor. Together, these data suggest that JNK phosphorylation of MAP2 plays an important role in defining dendritic architecture in the brain.

Key words: JNK; MAP2; dendrite; neuron; morphology; phosphorylation

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Received Dec 20, 2004; revised May 19, 2005; accepted May 19, 2005.

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