Several events during the normal development of the mammalian neocortex depend on N-cadherin, including the radial migration of immature projection neurons into the cortical plate. Remarkably, radial migration requires the N-cadherin extracellular domain but not N-cadherin-dependent homophilic cell-cell adhesion, suggesting that other N-cadherin-binding proteins may be involved. We used proximity ligation and affinity purification proteomics to identify N-cadherin-binding proteins. Both screens detected MycBP2 and SPRY domain protein Fbxo45, two components of an intracellular E3 ubiquitin ligase. Fbxo45 appears to be secreted by a nonclassical mechanism, not involving a signal peptide and not requiring transport from the endoplasmic reticulum to the Golgi apparatus. Fbxo45 binding requires N-cadherin SPRY motifs that are not involved in cell-cell adhesion. SPRY mutant N-cadherin does not support radial migration in vivo Radial migration was similarly inhibited when Fbxo45 expression was suppressed. The results suggest that projection neuron migration requires both Fbxo45 and the binding of Fbxo45 or another protein to SPRY motifs in the extracellular domain of N-cadherin.

中文翻译：

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Fbxo45在N-钙黏着蛋白的胞外域中绑定SPRY母题，并调节大脑发育过程中的神经元迁移。

哺乳动物新皮层正常发育过程中的一些事件取决于N-钙黏着蛋白，包括未成熟的投射神经元径向迁移到皮层板中。值得注意的是，径向迁移需要N-钙粘着蛋白胞外域，而不需要N-钙粘着蛋白依赖的同质性细胞间粘附，这表明可能还涉及其他N-钙粘着蛋白结合蛋白。我们使用邻近连接和亲和纯化蛋白质组学来鉴定N-钙粘着蛋白结合蛋白。两次筛选均检测到MycBP2和SPRY域蛋白Fbxo45，它们是细胞内E3泛素连接酶的两个组成部分。Fbxo45似乎是由非经典机制分泌的，不涉及信号肽，不需要从内质网运输到高尔基体。Fbxo45绑定需要不参与细胞粘附的N-钙粘着蛋白SPRY基序。SPRY突变N-钙粘着蛋白不支持体内径向迁移当Fbxo45表达被抑制时，径向迁移同样受到抑制。结果表明，投射神经元迁移既需要Fbxo45，又需要Fbxo45或另一种蛋白质与N-钙粘蛋白胞外域中的SPRY基序结合。