ABSTRACT
During development of the mammalian neocortex, the orientation of migrating multipolar projection neurons is controlled by Reelin, a secreted glycoprotein, which increases cell-surface expression of N-cadherin. Although N-cadherin regulates cell-cell adhesion, recent results suggest that its adhesive function is not required to orient multipolar neuron migration. To understand N-cadherin function in multipolar migration, we performed two independent screens for embryonic brain proteins that bind the N-cadherin extracellular domain. Both screens detected MycBP2 and SPRY-domain protein Fbxo45, two components of an intracellular E3 ubiquitin ligase. We found that Fbxo45 is secreted by a non-classical mechanism, not involving a signal peptide and not requiring endoplasmic reticulum to Golgi transport. Secreted Fbxo45 stimulated neurite branching in culture. A SPRY-motif N-cadherin mutant did not bind Fbxo45 and failed to rescue neuron migration even though it still formed trans-homophilic adhesions. The results suggest that secreted Fbxo45 may regulate neurite branching and bind N-cadherin to orient multipolar neuron migration.
