EphB1 controls proper long-range cortical axon guidance through a cell non-autonomous role in GABAergic cells

Abstract

ABSTRACTEphB1 is required for proper guidance of cortical long-range axon projections during brain development, but how EphB1 regulates this process remains unclear. To determine the relevant cell types in which EphB1 functions for proper cortical axon guidance, we generated a new floxed EphB1 mouse. We show here that EphB1 conditional knockout (cKO) in most of the developing cortical excitatory neurons (Emx1-Cre) failed to produce cortical axon guidance defects. However, EphB1 cKO in GABAergic cell populations (Vgat-Cre or dlx1/2-Cre) reproduced fully the cortical axon guidance defects observed in global EphB1-/- mice. Interestingly, in the EphB1 cKOVgat mice, the misguided axon bundles in the dorsal striatum contained comingled striatal GABAergic and cortical glutamatergic axons. Surprisingly, conditional loss of EphB1 in D1 or D2 dopamine receptor-expressing populations did not produce the cortical axon guidance defects, and no D1-or D2-SPN axons were detected within the misguided axon bundles of EphB1 KO mice. In contrast, parvalbumin-positive GABAergic cell axons were observed in the misguided axon bundles in EphB1 KO mice. Finally, a large fraction of the ectopic axons in EphB1 KO mice were in close apposition to the major blood vessels in the ventral telencephalon, suggesting that EphB1 expression in GABAergic cells normally promotes avoidance of these ectopic long-range axons from the developing cerebral vasculature. Together, our data reveal a new role for EphB1 in GABAergic cells to influence proper cortical glutamatergic long-range axon guidance during early brain development.