Establishment of high reciprocal connectivity between clonal cortical neurons is regulated by the Dnmt3b DNA methyltransferase and clustered protocadherins.
Establishment of high reciprocal connectivity between clonal cortical neurons is regulated by the Dnmt3b DNA methyltransferase and clustered protocadherins.
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DOI：
10.1186/s12915-016-0326-6
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发表时间：
2016-12-02
期刊：
影响因子：
5.4
通讯作者：
Yoshimura Y
中科院分区：
文献类型：
--
作者：
Tarusawa E;Sanbo M;Okayama A;Miyashita T;Kitsukawa T;Hirayama T;Hirabayashi T;Hasegawa S;Kaneko R;Toyoda S;Kobayashi T;Kato-Itoh M;Nakauchi H;Hirabayashi M;Yagi T;Yoshimura Y
突触连接的特异性是神经回路正常运作的基础。在相当程度上，在没有感觉经验的情况下，在感觉皮层中建立起信息处理的特定神经元连接，然后通过感觉经验单独地完善这些连接。来自同一个祖细胞的兴奋性神经元在出生后的皮层中优先连接，这表明细胞谱系有助于神经元的初始连接。然而，谱系依赖性连接特异性的出生后发育过程尚不清楚，也不清楚来自同一神经干细胞的克隆神经元如何被标记为其共同神经干细胞的身份并被引导形成突触连接。我们发现，来自同一神经干细胞并位于同一层的皮层兴奋性神经元在小鼠桶状皮层中优先建立相互突触连接。我们观察到克隆而非克隆神经元对之间的突触连接在出生后发育期间短暂增加，随后是克隆神经元对之间相互连接的选择性稳定。此外，我们证明克隆神经元对之间相互连接的选择性稳定性受到DNA甲基转移酶3b （Dnmt3b）缺乏的损害，Dnmt3b决定了早期皮质发生过程中干细胞基因的DNA甲基化模式。Dnmt3b调节聚集型原钙粘蛋白（cPcdh）异构体的出生后表达，cPcdh是一个粘附分子家族。我们发现克隆神经元对的cPcdh缺乏会损害连接形成和稳定的整个过程，从而建立谱系特异性连接互惠。我们的研究结果表明，在出生后发育过程中，桶状皮质第4层的克隆神经元之间选择性地形成并保留了局部的、互惠的神经连接，Dnmt3b和cPcdhs是建立谱系特异性互惠连接所必需的。这些发现表明，谱系特异性连接互惠在胚胎发育期间由Dnmt3b预先确定，并且cpcdh有助于出生后皮层神经元识别，以指导新皮层中谱系依赖性突触连接。本文的在线版本（doi:10.1186/s12915-016-0326-6）包含补充材料，可供授权用户使用。
The specificity of synaptic connections is fundamental for proper neural circuit function. Specific neuronal connections that underlie information processing in the sensory cortex are initially established without sensory experiences to a considerable extent, and then the connections are individually refined through sensory experiences. Excitatory neurons arising from the same single progenitor cell are preferentially connected in the postnatal cortex, suggesting that cell lineage contributes to the initial wiring of neurons. However, the postnatal developmental process of lineage-dependent connection specificity is not known, nor how clonal neurons, which are derived from the same neural stem cell, are stamped with the identity of their common neural stem cell and guided to form synaptic connections. We show that cortical excitatory neurons that arise from the same neural stem cell and reside within the same layer preferentially establish reciprocal synaptic connections in the mouse barrel cortex. We observed a transient increase in synaptic connections between clonal but not nonclonal neuron pairs during postnatal development, followed by selective stabilization of the reciprocal connections between clonal neuron pairs. Furthermore, we demonstrate that selective stabilization of the reciprocal connections between clonal neuron pairs is impaired by the deficiency of DNA methyltransferase 3b (Dnmt3b), which determines DNA-methylation patterns of genes in stem cells during early corticogenesis. Dnmt3b regulates the postnatal expression of clustered protocadherin (cPcdh) isoforms, a family of adhesion molecules. We found that cPcdh deficiency in clonal neuron pairs impairs the whole process of the formation and stabilization of connections to establish lineage-specific connection reciprocity. Our results demonstrate that local, reciprocal neural connections are selectively formed and retained between clonal neurons in layer 4 of the barrel cortex during postnatal development, and that Dnmt3b and cPcdhs are required for the establishment of lineage-specific reciprocal connections. These findings indicate that lineage-specific connection reciprocity is predetermined by Dnmt3b during embryonic development, and that the cPcdhs contribute to postnatal cortical neuron identification to guide lineage-dependent synaptic connections in the neocortex. The online version of this article (doi:10.1186/s12915-016-0326-6) contains supplementary material, which is available to authorized users.
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