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The extracellular matrix molecule reelin is a crucial molecule in CNS development, in particular in the cerebellum and cerebral cortex. In the cerebral cortex, reelin is provided by a small number of neurons located in the marginal zone (MZ). These neurons belong to the earliest neurons generated, but little is known about the molecular mechanisms of their specification. Here we describe that reelin-positive cells are strongly increased in the developing cortex of thePax6mutant miceSmall eye. Shortly after the onset of reelin expression, the number of reelin- and calretinin-positive cells is doubled in the cortex ofPax6mutants and this increase is further enhanced during development. In contrast, calbindin-positive cells in the MZ do not co-express reelin and are not altered in thePax6mutant cortex. The split of the preplate cells was also defective in thePax6mutant cortex, suggesting that the amount of reelin is crucial for positioning of the cortical plate between the MZ and subplate. We further show thatPax6mutant cortical cells isolatedin vitrodo not develop an increase in reelin-positive cells, while cells isolated from the entire telencephalon do. Consistent with non-cell-autonomous mechanisms contributing to the increase in reelin-positive cells in the Pax6-deficient cortex, tangential migration of diverse cell types from the ventral telencephalon into the cortex is enhanced in thePax6mutant mice. Taken together, these experiments further elucidate how patterning of the forebrain by the transcription factor Pax6 regulates the specification of distinct neuronal subtypes in the cortical MZ.