Protocadherin clusters and cell adhesion kinase regulate dendrite complexity through Rho GTPase.
Protocadherin clusters and cell adhesion kinase regulate dendrite complexity through Rho GTPase.
复制标题
原钙粘蛋白簇和细胞粘附激酶通过 Rho GTPase 调节树突复杂性。
DOI：
10.1093/jmcb/mjs034
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发表时间：
2012-06
期刊：
影响因子：
--
通讯作者：
Wu, Q.
中科院分区：
文献类型：
--
作者：
Suo, L.;Lu, H.;Ying, G.;Capecchi, MR.;Wu, Q.
树突模式和脊柱形态发生对于神经回路的组装至关重要，以确保正常的大脑发育和突触连接，以及理解神经精神疾病和认知障碍的潜在机制。Rho GTPase家族通过调节和重组细胞骨架对神经元形态发生和突触可塑性至关重要。在这里，我们报道了原钙粘蛋白（Pcdh）簇和细胞粘附激酶（CAKs）在树突发育和脊柱发育中发挥重要作用。在体内和体外培养的海马原代神经元中，敲除整个Pcdhα簇导致CA1锥体神经元的树突简化和脊柱丢失。整个Pcdhγ簇的敲除或与Pcdhα的敲除联合导致体外类似的树突和脊柱缺陷。富含脯氨酸的酪氨酸激酶2 （Pyk2，也称为CAKβ、RAFTK、FAK2和CADTK）的过表达概括了这些缺陷，其敲低挽救了表型。此外，Pcdhα簇的基因缺失导致Pyk2和focal adhesion kinase （Fak）的磷酸化和激活，以及Rho GTPases的抑制。最后，Pyk2的过表达导致Rac1失活，相反，组成型活性Rac1挽救了Pcdhα簇敲除和Pcdhγ簇敲除引起的树突和脊柱形态发生缺陷。因此，Pcdh-CAK-Rho GTPase通路在树突发育和脊柱形态发生中的参与对大脑中神经元连接的正确组装具有有趣的意义。
Dendritic patterning and spine morphogenesis are crucial for the assembly of neuronal circuitry to ensure normal brain development and synaptic connectivity as well as for understanding underlying mechanisms of neuropsychiatric diseases and cognitive impairments. The Rho GTPase family is essential for neuronal morphogenesis and synaptic plasticity by modulating and reorganizing the cytoskeleton. Here, we report that protocadherin (Pcdh) clusters and cell adhesion kinases (CAKs) play important roles in dendritic development and spine elaboration. The knockout of the entire Pcdhα cluster results in the dendritic simplification and spine loss in CA1 pyramidal neurons in vivo and in cultured primary hippocampal neurons in vitro. The knockdown of the whole Pcdhγ cluster or in combination with the Pcdhα knockout results in similar dendritic and spine defects in vitro. The overexpression of proline-rich tyrosine kinase 2 (Pyk2, also known as CAKβ, RAFTK, FAK2, and CADTK) recapitulates these defects and its knockdown rescues the phenotype. Moreover, the genetic deletion of the Pcdhα cluster results in phosphorylation and activation of Pyk2 and focal adhesion kinase (Fak) and the inhibition of Rho GTPases in vivo. Finally, the overexpression of Pyk2 leads to inactivation of Rac1 and, conversely, the constitutive active Rac1 rescues the dendritic and spine morphogenesis defects caused by the knockout of the Pcdhα cluster and the knockdown of the Pcdhγ cluster. Thus, the involvement of the Pcdh-CAK-Rho GTPase pathway in the dendritic development and spine morphogenesis has interesting implications for proper assembly of neuronal connections in the brain.
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影响因子：
10.5
作者：
T. Yagi;M. Takeichi
通讯作者：
T. Yagi;M. Takeichi
DOI：
10.1523/jneurosci.4681-08.2009
发表时间：
2009-06-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Shi Y;Pontrello CG;DeFea KA;Reichardt LF;Ethell IM
通讯作者：
Ethell IM
影响因子：
5.7
作者：
L. Aelst;H. Cline
通讯作者：
L. Aelst;H. Cline
影响因子：
7.5
作者：
Tomar A;Schlaepfer DD
通讯作者：
Schlaepfer DD
DOI：
10.1073/pnas.50.4.703
发表时间：
1963-01-01
影响因子：
11.1
作者：
SPERRY, RW
通讯作者：
SPERRY, RW