The surface of the mammalian brain (the neocortex) contains six distinct layers of neurons. The extracellular matrix protein reelin regulates the migration of the neurons that form these layers. Reelin has two receptors:very low density lipoprotein receptor (Vldlr) and apolipoprotein E receptor 2(ApoER2). Now, Hack and colleagues reveal divergent roles for these two receptors in the migration of cortical neurons (see ). In mice,the order of the cortical layers is inverted in reelin-knockout mutants and in ApoER2 Vldlr double-knockout mutants; the phenotype of single-receptor knockouts is much milder. To determine the specific role of each reelin receptor in neuronal migration, the researchers mapped the fate of newly generated cortical neurons in single and double receptor mutants. Their results indicate that the proper migration of late-generated neurons, which form the superficial layers of the neocortex, requires ApoER2. Vldlr, by contrast, mediates a reelin stop signal that prevents neurons migrating into the cell-poor marginal zone that covers the neocortex.
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