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The gene tailless (tlx) encodes a forebrain-restricted transcription factor that is robustly expressed in progenitor cells of the ventricular and subventricular zones during neurogenesis. To investigate the role of tlx in neocortical development we generated a targeted deletion of tlx by homologous recombination. Here we compared the lamination, connectivity and patterning of cortical regions in adult tlx−/− mice and their wild-type littermates. We found first that neocortical thickness is reduced by 20% in mutant animals; most of this reduction is due to a diminution of supragranular layers, while layer I and layers IV through VI are relatively intact cytoarchitecturally. Consistent with this, the cross-sectional area of the corpus callosum is reduced by over 40%. Second, thalamocortical and intrinsic excitatory circuits in tlx−/− mice exhibit an essentially normal distribution from layer IV to the white matter, but are reduced superficial to layer IV. Finally, within parietal cortex of mutant mice a vibrissa-like pattern of cortical barrels is present in the expected rostro-caudal location. These observations indicate that loss of tlx function most severely affects generation and differentiation of neurons destined for superficial cortical layers. Thus, tlx may be important in sustaining the progenitor cell population throughout late prenatal development. Establishment of functional cortical areas, and development of basic patterns of thalamocortical and intra-cortical circuits occurs independently of tlx function.