ADP ribosylation factor 4 (Arf4) regulates radial migration through N-cadherin trafficking during cerebral cortical development.

Abstract

During the development of the cerebral cortex, N-cadherin plays a crucial role in facilitating radial migration by enabling cell-to-cell adhesion between migrating neurons and radial glial fibers or Cajar-Reztius cells. ADP ribosylation factor 4 (Arf4) and Arf5, which belong to the class II Arf small GTPase subfamily, control membrane trafficking in the endocytic and secretory pathways. However, their specific contribution to cerebral cortex development remains unclear. In this study, we sought to investigate the functional involvement of class II Arfs in radial migration during the layer formation of the cerebral cortex using mouse embryos and pups. Our findings indicate that knockdown of Arf4, but not Arf5, resulted in the stalling of transfected neurons with disorientation of the Golgi in the upper intermediate zone (IZ) and reduction in the migration speed in both the IZ and cortical plate. Migrating neurons with Arf4 knockdown exhibited cytoplasmic accumulation of N-cadherin, along with disturbed organelle morphology and distribution. Furthermore, supplementation of exogenous N-cadherin partially rescued the migration defect caused by Arf4 knockdown. In conclusion, our results suggest that Arf4 plays a crucial role in regulating radial migration via N-cadherin trafficking during cerebral cortical development.Significance StatementIn the cortical layer formation, the distribution of N-cadherin on cell surface in migrating neurons is tightly regulated by endosomal trafficking system. However, its molecular detail remained fully understood. Here, we demonstrated that Arf4 small GTPase, a critical regulator of membrane trafficking in the trans-Golgi network (TGN), plays distinct roles from Arf5 in radial migration. We further demonstrated that Arf4 regulates N-cadherin trafficking in and out of the TGN and the contact of migrating neurons with radial fibers. Our results suggest that Arf4 regulates radial migration through N-cadherin trafficking in the TGN.