The Serine/Threonine Kinase Ndr2 Controls Integrin Trafficking and Integrin-Dependent Neurite Growth
The Serine/Threonine Kinase Ndr2 Controls Integrin Trafficking and Integrin-Dependent Neurite Growth
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DOI：
10.1523/jneurosci.2728-13.2014
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发表时间：
2014-04-09
影响因子：
5.3
通讯作者：
Stork, Oliver
中科院分区：
文献类型：
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作者：
Rehberg, Kati;Kliche, Stefanie;Stork, Oliver
整合素参与神经系统发育的多种过程，包括神经细胞的增殖、迁移和分化。在这项研究中，我们发现丝氨酸/苏氨酸激酶Ndr2控制整合素依赖性小鼠海马神经元的树突和轴突生长。我们进一步证明，Ndr2能够诱导β 1整合素的活性和运输相关位点Thr（788/789）的磷酸化，从而刺激β 1整合素的PKC和camkii依赖性激活，以及它们的胞外分泌。因此，Ndr2与初级海马神经元中整合素阳性的早期和循环内体相关，激活的β 1整合素在Ndr2缺失神经元树突上的表面表达减少。Ndr2在树突分化中的作用在体内也很明显，因为Ndr2缺失突变小鼠在海马中表现出树突复杂性的特异性改变。这表明Ndr2在树突生长的精细调控中起作用；事实上，用Semaphorin 3A处理原代神经元可以挽救Ndr2敲除诱导的树突生长缺陷，但不能使生长超出控制水平。相应的，ndr2缺失突变小鼠在海马中表现出类似Semaphorin 3A（-/-）的过早树突分支表型。本研究结果表明，ndr2介导的整合素运输和激活在神经元发育过程中对神经突生长和引导信号至关重要。
Integrins have been implicated in various processes of nervous system development, including proliferation, migration, and differentiation of neuronal cells. In this study, we show that the serine/threonine kinase Ndr2 controls integrin-dependent dendritic and axonal growth in mouse hippocampal neurons. We further demonstrate that Ndr2 is able to induce phosphorylation at the activity-and trafficking-relevant site Thr(788/789) of beta 1-integrin to stimulate the PKC- and CaMKII-dependent activation of beta 1-integrins, as well as their exocytosis. Accordingly, Ndr2 associates with integrin-positive early and recycling endosomes in primary hippocampal neurons and the surface expression of activated beta 1-integrins is reduced on dendrites of Ndr2-deficient neurons. The role of Ndr2 in dendritic differentiation is also evident in vivo, because Ndr2-null mutant mice show arbor-specific alterations of dendritic complexity in the hippocampus. This indicates a role of Ndr2 in the fine regulation of dendritic growth; in fact, treatment of primary neurons with Semaphorin 3A rescues Ndr2 knock-down-induced dendritic growth deficits but fails to enhance growth beyond control level. Correspondingly, Ndr2-null mutant mice show a Semaphorin 3A(-/-)-like phenotype of premature dendritic branching in the hippocampus. The results of this study show that Ndr2-mediated integrin trafficking and activation are crucial for neurite growth and guidance signals during neuronal development.