A novel secretory pathway has been identified in the study of mice homozygous for the RelnOrl mutation, a line characterised by the defective secretion of the large extracellular matrix glycoprotein Reelin. By using both light and electron microscopy, immunohistochemical studies for Reelin in these mutants identified morphological changes in their Cajal-Retzius cells (CR cells). The CR cells of the mutant displayed the characteristic features of bipolar, tangentially elongated neurons with a dendritic proximal pole and an axonal cone at the opposite end of the soma. At either pole, cisterns of prominent rough endoplasmic reticulum (RER) were found to be rich in Reelin. However, the Reelin-positive RER cisterns of the axonal cones were hugely dilated in homozygous RelnOrl mice as compared with their wild type counterparts. CR cell axons displayed beads throughout their length, each contained a smooth spheroidal cistern filled with Reelin-immunoreactive fibrillar material, and were increased in number and size in RelnOrl mice. RER phenotype was rescued in the RelnAlb2 mice, a mutation in which no Reelin protein is produced. We propose that the RER dilations viewed in the RelnOrl mutation are due to the accumulation of the defective Reelin protein, and the large axonal beads in RelnOrl mice reflect the accumulation of truncated Reelin as the result of defects in its secretion. These observations point to an original, hitherto unrecognised, mechanism of secretion by bulk transport in smooth cisterns from the axonal cone into the axon, followed by secretion in the cortical marginal zone from the axonal cisterns that we have named axonal reelin reservoirs. J. Comp. Neurol. 440:136–143, 2001. © 2001 Wiley-Liss, Inc.