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

Abstract

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 JNK1Ϫ/Ϫ 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 JNK1Ϫ/Ϫ 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 (JNK1Ϫ/Ϫ 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.

Rapid regulation of microtubule-associated protein 2 in dendrites of nucleus laminaris of the chick following deprivation of afferent activity

“…Among all post-translational modifications of MAP2, phosphorylation is probably the most relevant to extracellular signals (for review, see Sánchez et al, 2000). MAP2 has been found to be a substrate for many protein kinases and phosphatases, including c-Jun N-terminal kinase1 (JNK1) and stathmin, whose phosphorylations of MAPs are important in defining neuronal dendritic structure (Björkblom et al, 2005;Ohkawa et al, 2007).…”

Ionizing radiation induces apoptosis and inhibits neuronal differentiation in rat neural stem cells via the c-Jun NH2-terminal kinase (JNK) pathway

“…However, sustained and systemic JNK inhibition may cause various adverse side effects, because JNK also have other important functions in the development, differentiation, and insulin resistance (Figure 7b) (Waetzig and Herdegen, 2005). For example, JNK1 À/À mice showed severe impairment in the architecture of the brain, indicating that JNK phosphorylates microtubuleassociated proteins and contributes to normal brain functions (Chang et al, 2003;Bjorkblom et al, 2005). Therefore, Waetzig and Herdegen (2005) proposed the context-specific inhibition of JNK, that is, specific inhibition of damaging actions of JNK.…”

Isoform-specific palmitoylation of JNK regulates axonal development

“…The actin depolymerizers Cyt.D (1 mM) and Lat.A (1 mM) were obtained from Calbiochem (San Diego, CA, USA). [9, H] palmitic acid (57 Ci/mmol) and biotin (Btn)-BMCC were purchased from PerkinElmer Life Sciences (Waltham, MA, USA). Optiprep was purchased from Axis Shield (Dundee, Scotland).…”

“…[3][4][5][6] However, accumulating evidence supports a physiological role of JNK in regulating neurite formation and morphogenesis. [7][8][9][10][11][12] Pharmacological inhibition of JNK activity blocks axogenesis in hippocampal neurons, arguing for an essential role of JNK in neurite development. 13 Growth factors and signalling molecules, including secreted proteins of the Wnt family, have also been found to activate JNK for remodelling dendrites and axons, a process that relies on cytoskeletal rearrangement.…”