Identification of small molecules that interfere with radial neuronal migration and early cortical plate development.

Using a fetal brain slice culture system that recapitulates early cortical plate (CP) development, we screened the "Diversity Set" chemical library from the National Cancer Institute in order to identify molecules that interfere with radial migration and CP formation and identified 11 candidate molecules. Although most compounds had broadly similar effects, histological and immunohistochemical studies with preplate and neuronal differentiation markers disclosed some differences in the anomalies induced, suggesting that the identified molecules may act on different targets. Selected compounds were tested for activity on signaling pathways known to be important during radial migration and CP development, namely reelin, phosphatidylinositol 3-kinase/Akt-protein kinase B(PKB)/glycogen synthase kinase-3ss (GSK3beta), atypical protein kinases C (aPKC), and Cdk5. No perturbation of reelin signaling or GSK3beta activity was detected. One molecule decreased the phosphorylation of Akt and focal adhesion kinase and may act via direct or indirect inhibition of Cdk5, whereas another inhibited phosphorylation of aPKCzeta/lambda and may interfere with cell polarity and leading edge formation or progression. These molecules potentially provide new tools to study a neuronal migration and CP development.