Axon Mediated Interneuron Migration

Abstract

Mammalian forebrain development requires extensive cell migration for cells to reach their appropriate location in the adult brain. Defects in this migration result in human malformations and neurologic deficits. Thus, understanding the mechanisms underlying normal cell migration during development is essential to understanding the pathogenesis of human malformations. Radial glia are known to support radial cell migration, while axons have been proposed as substrate for some non-radially migrating cells. Herein we have directly tested the hypothesis that axons can support non-radial cell migration. One population of cells known to migrate non-radially is the inhibitory interneurons that move from the ganglionic eminence to the cerebral cortex. We first show that early born GABAergic cells colocalize with TAG-1-positive (TAG-1+) axons, while later born cells colocalize with intermediate weight neurofilament-positive, TAG-1-negative (TAG-1-) processes, suggesting temporal differences in substrate specificities. We next developed an in vitro assay that allows us to observe cell migration on axons in culture. Using this assay we find that early born medial ganglionic eminence-derived interneurons migrate preferentially on TAG-1+ axons, while later born cells only migrate on neurofilament-positive/TAG-1- processes. These data provide the first direct evidence that ganglionic eminence cells migrate on axons and that there is an age-dependent substrate preference. Furthermore, the assay developed and characterized herein provides a robust method to further study the molecular substrates and guidance cues of axonophilic cell migration in neural development.