A genome-wide screen of CREB occupancy identifies the RhoA inhibitors Par6C and Rnd3 as regulators of BDNF-induced synaptogenesis.
A genome-wide screen of CREB occupancy identifies the RhoA inhibitors Par6C and Rnd3 as regulators of BDNF-induced synaptogenesis.
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DOI：
10.1371/journal.pone.0064658
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wayman GA
中科院分区：
文献类型：
--
作者：
Lesiak A;Pelz C;Ando H;Zhu M;Davare M;Lambert TJ;Hansen KF;Obrietan K;Appleyard SM;Impey S;Wayman GA
神经营养蛋白调节的基因表达被认为在突触结构的长期变化和树突棘的形成中发挥关键作用。脑源性神经营养因子 (BDNF) 已被证明可以诱导树突棘形成的增加，并且这一过程被认为部分是通过刺激 CREB 依赖性转录变化来发挥作用的。为了鉴定与 BDNF 诱导的突触发生相关的 CREB 调节基因，我们分析了海马神经元中 CREB 的转录占用情况。有趣的是，对海马 ChIP-Seq 数据的从头基序分析发现了一个非典型 CRE 基序 (TGGCG)，该基序在 CREB 目标区域富集并赋予 CREB 响应性。由于细胞骨架重塑是树突棘形成的重要组成部分，因此在我们的筛选中，我们将注意力集中在先前鉴定为 RhoA GTPase 抑制剂的基因上。生物信息分析确定了数十种已知可调节突触结构和功能的候选 CREB 靶基因。我们发现其中两个 RhoA 抑制剂 Par6C (Pard6A) 和 Rnd3 (RhoE) 是 BDNF 诱导的 CREB 调节基因。有趣的是，CREB 在 Rnd3 启动子区域占据了一簇非规范的 CRE 基序。最后，我们表明 BDNF 刺激的突触发生需要 Par6C 和 Rnd3 的表达，并且任一蛋白的过度表达都足以增加突触发生。因此，我们提出 BDNF 可以通过增加 RhoA 抑制剂 Par6C 和 Rnd3 的表达来调节功能性突触的形成。这项研究表明，CREB 靶基因的全基因组分析有助于发现新的突触发生调节因子。
Neurotrophin-regulated gene expression is believed to play a key role in long-term changes in synaptic structure and the formation of dendritic spines. Brain-derived neurotrophic factor (BDNF) has been shown to induce increases in dendritic spine formation, and this process is thought to function in part by stimulating CREB-dependent transcriptional changes. To identify CREB-regulated genes linked to BDNF-induced synaptogenesis, we profiled transcriptional occupancy of CREB in hippocampal neurons. Interestingly, de novo motif analysis of hippocampal ChIP-Seq data identified a non-canonical CRE motif (TGGCG) that was enriched at CREB target regions and conferred CREB-responsiveness. Because cytoskeletal remodeling is an essential element of the formation of dendritic spines, within our screens we focused our attention on genes previously identified as inhibitors of RhoA GTPase. Bioinformatic analyses identified dozens of candidate CREB target genes known to regulate synaptic architecture and function. We showed that two of these, the RhoA inhibitors Par6C (Pard6A) and Rnd3 (RhoE), are BDNF-induced CREB-regulated genes. Interestingly, CREB occupied a cluster of non-canonical CRE motifs in the Rnd3 promoter region. Lastly, we show that BDNF-stimulated synaptogenesis requires the expression of Par6C and Rnd3, and that overexpression of either protein is sufficient to increase synaptogenesis. Thus, we propose that BDNF can regulate formation of functional synapses by increasing the expression of the RhoA inhibitors, Par6C and Rnd3. This study shows that genome-wide analyses of CREB target genes can facilitate the discovery of new regulators of synaptogenesis.
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影响因子：
16.2
作者：
Ahn, S;Ginty, DD;Linden, DJ
通讯作者：
Linden, DJ
DOI：
10.1073/pnas.95.21.12202
发表时间：
1998-10-13
影响因子：
11.1
作者：
De Cesare, D;Jacquot, S;Sassone-Corsi, P
通讯作者：
Sassone-Corsi, P
DOI：
10.1073/pnas.0710213105
发表时间：
2008-01-08
影响因子：
11.1
作者：
Jiang, Xin;Lautermilch, Nathan J.;Catterall, William A.
通讯作者：
Catterall, William A.
影响因子：
3.5
作者：
Impey, Soren;Davare, Monika;Lasiek, Adam;Fortin, Dale;Ando, Hideaki;Varlamova, Olga;Obrietan, Karl;Soderling, Thomas R.;Goodman, Richard H.;Wayman, Gary A.
通讯作者：
Wayman, Gary A.
影响因子：
2.5
作者：
CAESER, M;AERTSEN, AD
通讯作者：
AERTSEN, AD