Abstract. We have expressed in neuroendocrine PC12 cells the polymeric immunoglobulin receptor (pIgR), which is normally targeted from the basolateral to the apical surface of epithelial cells. In the presence of nerve growth factor, PC12 cells extend neurites which contain synaptic vesicle-like structures and regulated secretory granules. By immunofluorescence microscopy, pIgR, like the synaptic vesicle protein synaptophysin, accumulates in both the cell body and the neurites. On the other hand, the transferrin receptor, which normally recycles at the basolateral surface in epithelial cells, and the cation-independent mannose 6-phosphate receptor, a marker of late endosomes, are largely restricted to the cell body. pIgR internalizes ligand into endosomes within the cell body and the neurites, while uptake of ligand by the low density lipoprotein receptor occurs primarily into endosomes within the cell body. We conclude that transport of membrane proteins to PC12 neurites as well as to specialized endosomes within these processes is selective and appears to be governed by similar mechanisms that dictate sorting in epithelial cells. Additionally, two types of endosomes can be identified in polarized PC12 cells by the differential uptake of ligand, a housekeeping type in the cell bodies and a specialized endosome in the neurites. Recent findings suggest that specialized axonal endosomes in neurons are likely to give rise to synaptic vesicles (Mundigl, O., M. Matteoli, L. Daniell, A. Thomas-Reetz, A. Metcalf, R. Jahn, and P. De Camilli. 1993. J. Cell Biol. 122:1207-1221. Although plgR reaches the specialized endosomes in the neurites of PC12 cells, we find by subcellular fractionation that under a variety of conditions it is efficiently excluded from synaptic vesicle-like structures as well as from secretory granules.p LASMA membrane proteins that normally reside in axonal domains of neurons are selectively targeted to apical domains when expressed in epithelial cells, suggesting an overlap between epithelial and neuronal-targeting mechanisms (Dotti et al., 1991;Powell et al., 1991;Pietrini et al., 1994). The overlap may include endocytotic structures as well, since apical and axonal early endosomes do not accumulate internalized transferrin and so are different from the endosomes at the base of the epithelial cell and in the cell body of the neuron (Fuller and Simons, 1986;Hughson and Hopkins, 1990; Parton et al., 1992; Barroso and Sztul, 1994). Because the latter endosomes primarily recycle proteins involved in cell maintenance functions, we refer to them as housekeeping endosomes. Specialized endo- somes, on the other hand, operate in specialized regions of cells, such as the sub-apical cytoplasm, and appear to give rise to small tubulovesicular structures that fuse with the cell surface. Examples of such apicaUy recycling vesicles include those that contain the vasopressin-sensitive water channels in kidney collecting ductules (for review see Verkman, 1992), the gastrin-responsive H÷K+-ATPase in gastric parie...