ErbB4 promotes inhibitory synapse formation by cell adhesion, independent of its kinase activity.
ErbB4 promotes inhibitory synapse formation by cell adhesion, independent of its kinase activity.
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ErbB4 通过细胞粘附促进抑制性突触形成，与其激酶活性无关。
DOI：
10.1038/s41398-021-01485-6
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发表时间：
2021-06-29
影响因子：
6.8
通讯作者：
Li B
中科院分区：
文献类型：
--
作者：
Luo B;Liu Z;Lin D;Chen W;Ren D;Yu Z;Xiong M;Zhao C;Fei E;Li B
神经系统功能的精确控制下的突触的活力是极其关键的。人们一直在努力探索突触形成的细胞和分子机制。已经发现细胞粘附分子对于脑中的突触组装是重要的。许多跨粘附复合物已被确定可以调节兴奋性突触的形成。然而，很少有人知道抑制性突触的突触发生机制。ErbB 4是在中间神经元中富集的受体酪氨酸激酶。在此，我们发现在HEK 293 T细胞中过表达ErbB 4诱导共培养的原代海马神经元中的桥蛋白或GABAAR α1斑点。ErbB 4的这种诱导作用与其激酶活性无关。K751 M是ErbB 4的一个激酶死亡突变体，在共培养体系中也能诱导gphyrin或GABAAR α1斑点。我们进一步构建了K751 M基因敲入小鼠，发现纯合子在出生时是可行的，并且在大体脑结构上没有变化。K751 M和野生型小鼠的中间神经元和锥体神经元（PyN）上的抑制性突触的数量相当，但在ErbB 4-B4小鼠中减少。此外，ErbB 4可以通过ErbB 4的胞外RLD结构域与Slitrk 3（抑制性突触处的跨膜突触后蛋白）反式相互作用。RLD的缺失减弱了ErbB 4对桥蛋白或GABAAR α1斑点的诱导。最后，通过分泌型RLD中和Slitrk 3来破坏ErbB 4-Slitrk 3相互作用减少了对PyNs的抑制性突触，并损害了GABA能传递。这些结果表明，ErbB 4作为细胞粘附分子，通过与Slitrk 3相互作用并以激酶非依赖性方式促进PyNs上的抑制性突触形成，提供了ErbB 4在抑制性突触形成中的意想不到的机制。
The precise control of the nervous system function under the vitality of synapses is extremely critical. Efforts have been taken to explore the underlying cellular and molecular mechanisms for synapse formation. Cell adhesion molecules have been found important for synapse assembly in the brain. Many trans-adhesion complexes have been identified to modulate excitatory synapse formation. However, little is known about the synaptogenic mechanisms for inhibitory synapses. ErbB4 is a receptor tyrosine kinase enriched in interneurons. Here, we showed that overexpressing ErbB4 in HEK293T cells induced gephyrin or GABAAR α1 puncta in co-cultured primary hippocampal neurons. This induction of ErbB4 was independent of its kinase activity. K751M, a kinase-dead mutant of ErbB4, can also induce gephyrin or GABAAR α1 puncta in the co-culture system. We further constructed K751M knock-in mice and found that the homozygous were viable at birth and fertile without changes in gross brain structure. The number of interneurons and inhibitory synapses onto pyramidal neurons (PyNs) were comparable between K751M and wild-type mice but decreased in ErbB4-Null mice. Moreover, ErbB4 can interact in trans with Slitrk3, a transmembrane postsynaptic protein at inhibitory synapses, through the extracellular RLD domain of ErbB4. The deletion of RLD diminished the induction of gephyrin or GABAAR α1 puncta by ErbB4. Finally, disruption of ErbB4–Slitrk3 interaction through neutralization of Slitrk3 by secretable RLD decreased inhibitory synapses onto PyNs and impaired GABAergic transmission. These results identify that ErbB4, as a cell adhesion molecule, promotes inhibitory synapse formation onto PyNs by interacting with Slitrk3 and in a kinase-independent manner, providing an unexpected mechanism of ErbB4 in inhibitory synapse formation.
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影响因子：
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作者：
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DOI：
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发表时间：
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