Calcium activation of the LMO4 transcription complex and its role in the patterning of thalamocortical connections
Calcium activation of the LMO4 transcription complex and its role in the patterning of thalamocortical connections
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DOI：
10.1523/jneurosci.0618-06.2006
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发表时间：
2006-08-09
影响因子：
5.3
通讯作者：
Ghosh, Anirvan
中科院分区：
文献类型：
--
作者：
Kashani, Amir H.;Qiu, Zilong;Ghosh, Anirvan
神经元连接的持久变化需要钙依赖性基因表达。在这里，我们报告了 LIM 结构域 4 (LM04) 的鉴定，它是皮质神经元中钙依赖性转录的介体。通过电压敏感钙通道和 NMDA 受体的钙流入有助于突触诱导的 LMO4 介导的反式激活。 LMO4 介导的转录依赖于突触刺激下游的钙/钙调蛋白依赖性蛋白 (CaM) 激酶 IV 和微管相关蛋白 (MAP) 激酶的信号传导。免疫共沉淀实验表明，LMO4 可以与 cAMP 反应元件结合蛋白 (CREB) 形成复合物，并可以与 LIM 同源域蛋白 1 (CLIM1) 和 CLIM2 的辅因子相互作用。为了评估 LMO4 在体内的作用，我们使用 Cre-Lox 基因靶向策略检查了前脑中 lmo4 条件性缺失的后果。在小鼠皮层中条件性删除 lmo4 的情况下，体感皮层中桶状区域的组织被破坏。具体而言，与对照相比，条件性lmo4缺失小鼠中的丘脑皮质传入神经未能分离成不同的桶特异性域。这些观察结果表明，LMO4 是一种钙依赖性反式激活因子，在发育过程中丘脑皮质连接模式中发挥着关键作用。
Lasting changes in neuronal connectivity require calcium-dependent gene expression. Here we report the identification of LIM domainonly 4 (LM04) as a mediator of calcium-dependent transcription in cortical neurons. Calcium influx via voltage-sensitive calcium channels and NMDA receptors contributes to synaptically induced LMO4-mediated transactivation. LMO4-mediated transcription is dependent on signaling via calcium/calmodulin-dependent protein (CaM) kinase IV and microtubule-associated protein (MAP) kinase downstream of synaptic stimulation. Coimmunoprecipitation experiments indicate that LMO4 can form a complex with cAMP response element-binding protein (CREB) and can interact with cofactor of LIM homeodomain protein 1 (CLIM1) and CLIM2. To evaluate the role of LMO4 in vivo, we examined the consequences of conditional loss of lmo4 in the forebrain, using the Cre-Lox gene-targeting strategy. The organization of the barrel field in somatosensory cortex is disrupted in mice in which lmo4 is deleted conditionally in the cortex. Specifically, in contrast to controls, thalamocortical afferents in conditional lmo4 null mice fail to segregate into distinct barrel-specific domains. These observations identify LMO4 as a calcium-dependent transactivator that plays a key role in patterning thalamocortical connections during development.