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<p>Abstract</p> <p>Background</p> <p>The secreted ligand Reelin is believed to regulate the translocation of prospective layer 6 (L6) neocortical neurons into the preplate, a loose layer of pioneer neurons that overlies the ventricular zone. Recent studies have also suggested that Reelin controls neuronal orientation and polarized dendritic growth during this period of early cortical development. To explicitly characterize and quantify how Reelin controls this critical aspect of neurite initiation and growth we used a new <it>ex utero</it> explant model of early cortical development to selectively label a subset of L6 cortical neurons for complete 3-D reconstruction.</p> <p>Results</p> <p>The total neurite arbor sizes of neurons in Reelin-deficient (<it>reeler</it> mutant) and Dab1-deficient (Reelin-non-responsive <it>scrambler</it> mutant) cortices were quantified and unexpectedly were not different than control arbor lengths (p = 0.51). For each mutant, however, arbor organization was markedly different: mutant neurons manifested more primary processes (neurites emitted directly from the soma) than wild type, and these neurites were longer and displayed less branching. <it>Reeler</it> and <it>scrambler</it> mutant neurites extended tangentially rather than radially, and the Golgi apparatus that normally invests the apical neurite was compact in both <it>reeler</it> and <it>scrambler</it> mutants. Mutant cortices also exhibited a neurite “exclusion zone” which was relatively devoid of L6 neuron neurites and extended at least 15 μm beneath the pial surface, an area corresponding to the marginal zone (MZ) in the wild type explants. The presence of an exclusion zone was also indicated in the orientation of mutant primary neurite and neuronal somata, which failed to adopt angles within ~20˚ of the radial line to the pial surface. Injection of recombinant Reelin to <it>reeler,</it> but not <it>scrambler</it>, mutant cortices fully rescued soma orientation, Golgi organization, and dendritic projection defects within four hrs.</p> <p>Conclusions</p> <p>These findings indicate Reelin promotes directional dendritic growth into the MZ, an otherwise exclusionary zone for L6 neurites.</p>