Aberrant Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity Is Associated with Abnormal Dendritic Spine Morphology in the ATRX Mutant Mouse Brain
Aberrant Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity Is Associated with Abnormal Dendritic Spine Morphology in the ATRX Mutant Mouse Brain
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DOI：
10.1523/jneurosci.4816-10.2011
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发表时间：
2011-01-05
影响因子：
5.3
通讯作者：
Fukunaga, Kohji
中科院分区：
文献类型：
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作者：
Shioda, Norifumi;Beppu, Hideyuki;Fukunaga, Kohji
在人类中，编码ATRX（蔗糖非发酵2家族的染色质重塑蛋白）的基因突变会导致几种精神发育迟滞疾病，包括α-地中海贫血X连锁精神发育迟滞综合征。我们产生了缺乏外显子2的ATRX突变小鼠（ATRX（Delta E2）小鼠），这是一种模拟人类患者中观察到的外显子2突变的突变，并与较轻形式的发育迟缓相关。ATRX（Delta E2）小鼠在内侧前额叶皮质（mPFC）中表现出异常的树突棘形成。与其他智力低下小鼠模型一致，与野生型小鼠相比，ATRX（Delta E2）小鼠表现出更长更细的树突棘，而棘数没有变化。有趣的是，在ATRX（Delta E2）小鼠的mPFC中观察到钙/钙调蛋白依赖性蛋白激酶II（CaMKII）活性异常增加。CaMKII自身磷酸化和活性的增加与Rac 1-鸟嘌呤核苷酸交换因子（GEF）T细胞淋巴瘤侵袭和转移1（Tiam 1）和卡林-7（CaMKII的已知底物）的磷酸化增加相关。我们证实了mPFC提取物中p21激活激酶（PAKs）的磷酸化增加。此外，在ATRX（Delta E2）小鼠的mPFC中，蛋白磷酸酶1（PP 1）的蛋白表达和活性明显降低。在培养的皮层神经元中，冈田酸抑制PP 1增加了CaMKII依赖的Tiam 1和kalirin-7磷酸化。总之，我们的数据强烈表明，异常CaMKII激活可能介导mPFC异常棘形成。在ATRX（Delta E2）小鼠中观察到的这种形态学变化加上Rac 1-GEF/PAK信号传导升高可能有助于在人类患者中观察到的精神发育迟滞综合征。
In humans, mutations in the gene encoding ATRX, a chromatin remodeling protein of the sucrose-nonfermenting 2 family, cause several mental retardation disorders, including alpha-thalassemia X-linked mental retardation syndrome. We generated ATRX mutant mice lacking exon 2 (ATRX(Delta E2) mice), a mutation that mimics exon 2 mutations seen in human patients and associated with milder forms of retardation. ATRX(Delta E2) mice exhibited abnormal dendritic spine formation in the medial prefrontal cortex (mPFC). Consistent with other mouse models of mental retardation, ATRX(Delta E2) mice exhibited longer and thinner dendritic spines compared with wild-type mice without changes in spine number. Interestingly, aberrant increased calcium/calmodulin-dependent protein kinase II (CaMKII) activity was observed in the mPFC of ATRX(Delta E2) mice. Increased CaMKII autophosphorylation and activity were associated with increased phosphorylation of the Rac1-guanine nucleotide exchange factors (GEFs) T-cell lymphoma invasion and metastasis 1 (Tiam1) and kalirin-7, known substrates of CaMKII. We confirmed increased phosphorylation of p21-activated kinases (PAKs) in mPFC extracts. Furthermore, reduced protein expression and activity of protein phosphatase 1 (PP1) was evident in the mPFC of ATRX(Delta E2) mice. In cultured cortical neurons, PP1 inhibition by okadaic acid increased CaMKII-dependent Tiam1 and kalirin-7 phosphorylation. Together, our data strongly suggest that aberrant CaMKII activation likely mediates abnormal spine formation in the mPFC. Such morphological changes plus elevated Rac1-GEF/PAK signaling seen in ATRX(Delta E2) mice may contribute to mental retardation syndromes seen in human patients.