Neural Stem Cells Direct Axon Guidance via Their Radial Fiber Scaffold

Neural stem cells directly or indirectly generate all neurons and macroglial cells and guide migrating neurons by using a palisade-like scaffold made of their radial fibers. Here, we describe an unexpected role for the radial fiber scaffold in directing corticospinal and other axons at the junction between the striatum and globus pallidus. The maintenance of this scaffold, and consequently axon pathfinding, is dependent on the expression of an atypical RHO-GTPase, RND3/RHOE, together with its binding partner ARHGAP35/P190A, a RHO GTPase-activating protein, in the radial glia-like neural stem cells within the ventricular zone of the medial ganglionic eminence. This role is independent of RND3 and ARHGAP35 expression in corticospinal neurons, where they regulate dendritic spine formation, axon elongation, and pontine midline crossing in a FEZF2-dependent manner. The prevalence of neural stem cell scaffolds and their expression of RND3 and ARHGAP35 suggests that these observations might be broadly relevant for axon guidance and neural circuit formation. [Display omitted] •Rnd3 is expressed by corticospinal neurons (CSNs) and radial glia/neural stem cells•FEZF2-driven Rnd3 expression helps CSNs to form dendritic spines and extend axons•RND3 and ARHGAP35 maintain the radial glial scaffold at the striatopallidal junction•The striatopallidal radial glial scaffold facilitates corticospinal axon pathfinding Kaur et al. show that the radial glial scaffold of neural stem cells from medial ganglionic eminence directs corticospinal and other axons through a previously unknown choice point at the striatopallidal junction in an RND3/ARHGAP35-dependent manner. Within corticospinal neurons, FEZF2-dependent Rnd3 expression regulates dendritic spinogenesis, axon elongation, and pontine midline crossing.