Fbxo45 Binds SPRY Motifs in the Extracellular Domain of N-Cadherin and Regulates Neuron Migration during Brain Development

Several events during the normal development of the mammalian neo- cortex 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 prox- imity ligation and affinity purification proteomics to identify N-cadherin-binding pro- teins. Both screens detected MycBP2 and SPRY domain protein Fbxo45, two compo- nents 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 projec- tion neuron migration requires both Fbxo45 and the binding of Fbxo45 or another protein to SPRY motifs in the extracellular domain of N-cadherin.