Populations of Radial Glial Cells Respond Differently to Reelin and Neuregulin1 in a Ferret Model of Cortical Dysplasia
UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD
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Radial glial cells play an essential role during corticogenesis through their function as neural precursors and guides of neuronal migration. Both reelin and neuregulin1 NRG1 maintain the radial glial scaffold they also induce expression of Brain Lipid Binding Protein BLBP, a well known marker of radial glia. Although radial glia in normal ferrets express both vimentin and BLBP, this coexpression diverges at P3 vimentin is expressed in the radial glial processes, while BLBP appears in cells detached from the ventricular zone. Our lab developed a model of cortical dysplasia in the ferret, resulting in impaired migration of neurons into the cortical plate and disordered radial glia. This occurs after exposure to the antimitotic methylazoxymethanol MAM on the 24th day of development E24. Ferrets treated with MAM on E24 result in an overall decrease of BLBP expression radial glia that continue to express BLBP, however, show only mild disruption compared with the strongly disrupted vimentin expressing radial glia. When E24 MAM-treated organotypic slices are exposed to reelin or NRG1, the severely disrupted vimentin radial glial processes are repaired but the slightly disordered BLBP processes are not. The realignment of vimentin processes was linked with an increase of their BLBP expression. BLBP expressing radial glia are distinguished by being both less affected by MAM treatment and by attempts at repair. We further investigated the effects induced by reelin and found that signaling was mediated via VLDLRDab1Pi3K activation while NRG1 signaling was mediated via erbB3erbB4Pi3K. We then tested whether radial glial repair correlated with improved neuronal migration. Repairing the radial glial scaffold is not sufficient to restore neuronal migration although reelin improves migration of neurons toward the cortical plate signaling through ApoER2Dab1Pi3K activation, NRG1 does not.
- Medicine and Medical Research