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
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
复制标题
DOI：
10.1523/jneurosci.1517-05.2005
复制
发表时间：
2005-07-06
影响因子：
5.3
通讯作者：
Coffey, ET
中科院分区：
文献类型：
--
作者：
Björkblom, B;Östman, N;Coffey, ET
神经系统的正常功能需要对树突形态和突触连接进行精确调控。在此，我们报道了c - Jun N -末端激酶1（JNK1）缺陷小鼠的小脑和运动皮层中树突结构受到严重损害。通过对候选介质进行无偏筛选，我们确定了树突特异性高分子量微管相关蛋白2（MAP2）是大脑中的一种JNK底物。随后我们表明，在完整细胞中MAP2可被JNK磷酸化，并且在JNK1 - / - 大脑中MAP2富含脯氨酸结构域的磷酸化水平降低。我们开发了靶向细胞区室的JNK抑制剂，以确定具有生理活性的胞质JNK池与树突结构之间是否存在功能关系。利用这些抑制剂，我们证明胞质中的JNK（而非细胞核中的JNK）决定了培养神经元的树突长度和分支复杂性。此外，我们证实激活JNK后，依赖于MAP2的突起伸长会增强。利用JNK1 - / - 神经元，我们揭示了在调节树突分支方面JNK1相对于ERK具有主导作用，而ERK仅在JNK活性较低的条件下（JNK1 - / - 神经元）调节树突形状。这些结果揭示了JNK和ERK之间一种新的拮抗作用，可能为精细调节树突分支提供了一种机制。总之，这些数据表明JNK对MAP2的磷酸化在确定大脑中的树突结构方面起着重要作用。
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.