Autonomous and non-autonomous roles for ephrin-B in interneuron migration

摘要

Abstract While several studies indicate the importance of ephrin-B/EphB bidirectional signaling in excitatory neurons, potential roles for these molecules in inhibitory neurons are largely unknown. We identify here an autonomous receptor-like role for ephrin-B reverse signaling in the tangential migration of interneurons into the neocortex using ephrin-B ( EfnB1/B2/B3 ) conditional triple mutant ( TM lz ) mice and a forebrain inhibitory neuron specific Cre driver. Inhibitory neuron deletion of the three EfnB genes leads to reduced interneuron migration, abnormal cortical excitability, and lethal audiogenic seizures. Truncated and intracellular point mutations confirm the importance of ephrin-B reverse signaling in interneuron migration and cortical excitability. A non-autonomous ligand-like role was also identified for ephrin-B2 that is expressed in neocortical radial glial cells and required for proper tangential migration of GAD65-positive interneurons. Our studies thus define both receptor-like and ligand-like roles for the ephrin-B molecules in controlling the migration of interneurons as they populate the neocortex and help establish excitatory/inhibitory (E/I) homeostasis. Graphical abstract Display Omitted Highlights ? All three ephrin-B's are expressed in inhibitory neurons in the developing brain. ? Receptor-like ephrin-B reverse signaling is required for interneuron migration. ? Ephrin-B2 is also expressed in cortical neurons and radial glial cells. ? Ligand-like ephrin-B2 forward signaling is also involved in interneuron migration. ? EphB/ephrin-B bidirectional signaling establishes excitatory-inhibitory homeostasis.