Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Cell Biol. 2018 Nov 5;217(11):4007-4024. doi: 10.1083/jcb.201803105. Epub 2018 Sep 5.
Neuronal connections are initiated by axon targeting to form synapses. However, how the maturation of axon terminals is modulated through interacting with postsynaptic elements remains elusive. In this study, we find that ligand of Numb protein X 1 (Lnx1), a postsynaptic PDZ protein expressed in hippocampal CA3 pyramidal neurons, is essential for mossy fiber (MF) axon targeting during the postnatal period. Lnx1 deletion causes defective synaptic arrangement that leads to aberrant presynaptic terminals. We further identify EphB receptors as novel Lnx1-binding proteins to form a multiprotein complex that is stabilized on the CA3 neuron membrane through preventing proteasome activity. EphB1 and EphB2 are independently required to transduce distinct signals controlling MF pruning and targeting for precise DG-CA3 synapse formation. Furthermore, constitutively active EphB2 kinase rescues structure of the wired MF terminals in mutant mice. Our data thus define a retrograde trans-synaptic regulation required for integration of post- and presynaptic structure that participates in building hippocampal neural circuits during the adolescence period.
神经元连接是通过轴突靶向形成突触而启动的。然而，轴突末梢的成熟是如何通过与突触后成分相互作用来调节的，目前仍不清楚。在这项研究中，我们发现 Numb 蛋白 X1（Lnx1）的配体，一种在海马 CA3 锥体神经元中表达的突触后 PDZ 蛋白，对于出生后时期的苔藓纤维（MF）轴突靶向是必不可少的。Lnx1 缺失导致突触排列缺陷，导致异常的突触前末梢。我们进一步鉴定 EphB 受体为新型 Lnx1 结合蛋白，形成一个多蛋白复合物，通过防止蛋白酶体活性稳定在 CA3 神经元膜上。EphB1 和 EphB2 独立地需要传递不同的信号，控制 MF 的修剪和靶向，以实现 DG-CA3 突触的精确形成。此外，组成性激活的 EphB2 激酶可挽救 突变小鼠中有线 MF 末梢的结构。因此，我们的数据定义了一种逆行跨突触调节，对于整合突触后和突触前结构是必需的，参与了青春期期间海马神经回路的构建。
