Formation of the substantia nigra requires Reelin-mediated fast, laterally-directed migration of dopaminergic neurons

Midbrain dopaminergic (mDA) neurons migrate to form the laterally-located substantia nigra pars compacta (SN) and medially-located ventral tegmental area (VTA), but little is known about the underlying cellular and molecular processes. Reelin signaling regulates tangential migration of SN-mDA neurons, but whether Reelin acts directly on SN-mDA neurons and how it affects their cellular morphology and migratory behavior has not been explored. Here we visualize the dynamic cell morphologies of tangentially migrating SN-mDA neurons with 3D-time-lapse imaging and identify two distinct migration modes. Slow migration is the default mode in SN-mDA neurons, while fast, laterally-directed migration occurs infrequently and is strongly associated with bipolar cell morphology. By speci1cally inactivating Reelin signaling in mDA neurons we demonstrate its direct role in SN-mDA tangential migration. We show that Reelin signaling promotes laterally-biased movements in mDA neurons during their slow migration mode, stabilizes leading process morphology and increases the probability of fast, laterally-directed migration.