(AMH) S U M M A R Y Tight junctions (TJs) form physical barriers in various tissues and regulate paracellular transport of ions, water, and molecules. Myelinating Schwann cells form highly organized structures, including compact myelin, nodes of Ranvier, paranodal regions, Schmidt-Lanterman incisures, periaxonal cytoplasmic collars, and mesaxons. Autotypic TJs are formed in non-compacted myelin compartments between adjacent membrane lamellae of the same Schwann cell. Using indirect immunofluorescence and RT-PCR, we analyzed the expression of adherens junction (E-cadherin) and TJ [claudins, zonula occludens (ZO)-1, occludin] components in human peripheral nerve endoneurium, showing clear differences with published rodent profiles. Adult nerve paranodal regions contained E-cadherin, claudin-1, claudin-2, and ZO-1. Schmidt-Lanterman incisures contained E-cadherin, claudin-1, claudin-2, claudin-3, claudin-5, ZO-1, and occludin. Mesaxons contained E-cadherin, claudin-1, claudin-2, claudin-3, ZO-1, and occludin. None of the proteins studied were associated with nodal inter-Schwann cell junctions. Fetal nerve expression of claudin-1, claudin-3, ZO-1, and occludin was predominantly punctate, with a mesaxonal labeling pattern, but paranodal (ZO-1, claudin-3) and Schmidt-Lanterman incisure (claudins-1 and -3) expression profiles typical of compact myelin were visible by gestational week 37. The clear differences observed between human and published rodent nerve profiles emphasize the importance of human studies when translating the results of animal models to human diseases. PERIPHERAL AXONS are isolated from the surrounding non-nervous tissues by a triple layer of collagen-based connective tissue, including the outermost epineurial layer, that surrounds the whole nerve, the perineurium, which surrounds nerve fascicles, and the innermost endoneurial layer that surrounds individual nerve fibers, and by a Schwann cell sheath. In adults, the Schwann cells form either a myelin sheath or an amyelin sheath. Myelinating Schwann cells wrap around the axon, forming highly organized, compacted, and noncompacted, multilamellar membrane structures. The non-compact structures include the paranodal loop regions, the Schmidt-Lanterman incisures, the periaxonal cytoplasmic collar, and the inner and outer mesaxons. At the nodes of Ranvier, interdigitations of the plasma membranes of adjacent Schwann cells assure the continuity of the Schwann cell sheath along the whole length of the axon, while a continuous, Schwann cell-derived basal lamina forms a permeable boundary between the endoneurial connective tissue layer and the Schwann cell myelin sheath (Thomas 1963).Perineurial cells of the perineurium form a selective diffusion barrier between the endoneurium and the epineurium (Thomas 1963;Jaakkola et al. 1993;Pummi et al. 2004), and we have previously shown that the tight junction (TJ) proteins zonula occludens (ZO)-1, occludin, claudin-1, and claudin-3 all contribute to the formation of this perineurial diffusion barrier in human Cor...