Endogenous Neuregulin Restores Radial Glia in a (Ferret) Model of Cortical Dysplasia

Abstract

Radial glia are integral components of the developing neocortex. During corticogenesis, they form an important scaffold for neurons migrating into the cortical plate. Recent attention has focused on neuregulin (NRG1), acting through erbB receptors, in maintaining their morphology. We developed a model of developmental radial glial disruption by delivering an antimitotic [methylazoxy methanol (MAM)] to pregnant ferrets on embryonic day 24 (E24). We previously found that normal ferret cortex contains a soluble factor capable of realigning the disorganized radial glia back toward their normal morphology. Characterization of the reorganizing activity in normal cortex demonstrated that the probable factor mediating these responses was a 30-50 kDa protein. To test whether this endogenous soluble factor was NRG1, we used organotypic cultures of E24 MAM-treated ferret neocortex supplemented with the endogenous factor obtained from normal cortical implants, exogenous NRG1beta, antibodies that either blocked or stimulated erbB receptors, or a soluble erbB subtype that binds to available NRG1. We report that exogenous NRG1 or antibodies that stimulate erbB receptors dramatically improve the morphology of disrupted radial glia, whereas blockade of NRG1-erbB signaling prevents the radial glial repair. Our results suggest that NRG1 is an endogenous factor in ferret neocortex capable of repairing damaged radial glia and that it acts via one or more erbB receptors.