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.
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.
Turku Centre for Biotechnology, Abo Akademi and Turku University, BioCity, FIN-20521 Turku, Finland.
Benny
B
Björkblom
Nina
N
Ostman
Vesa
V
Hongisto
Vladislav
V
Komarovski
Jan-Jonas
JJ
Filén
Tuula A
TA
Nyman
Tuula
T
Kallunki
Michael J
MJ
Courtney
Eleanor T
ET
Coffey
D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000201:enzymology; D002478:Cells, Cultured / Q000201:enzymology / Q000648:ultrastructure; D002525:Cerebellar Cortex / Q000166:cytology / Q000201:enzymology / Q000254:growth & development; D002522:Chlorocebus aethiops; D003600:Cytosol / Q000201:enzymology*; D003712:Dendrites / Q000648:ultrastructure*; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009044:Motor Cortex / Q000166:cytology / Q000201:enzymology; D009474:Neurons / Q000648:ultrastructure; D010766:Phosphorylation; D016548:Prosencephalon / Q000166:cytology / Q000201:enzymology; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection
D008869:Microtubule-Associated Proteins; D011993:Recombinant Fusion Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8