The membrane-associated cytoskeletal proteins, including protein 4.1 family, play important roles in membrane integrity, protein targeting, and signal transduction. Although protein 4.1G (4.1G) is expressed ubiquitously in mammalian tissues, it can have very discrete distributions within cells. The present study investigated the expression and distributions of 4.1G in rodent sciatic nerve. Northern and Western blot analysis detected abundant 4.1G mRNA and protein in rat sciatic nerve extracts. Immunohistochemical staining with a 4.1G-specific antibody and double immunolabeling with E-cadherin, beta IV spectrin, and connexin 32 detected 4.1G in paranodal loops, Schmidt-Lanterman incisures, and periaxonal, mesaxonal, and abaxonal membranes of rodent sciatic nerve. Immunoelectron microscopy confirmed the immunodistribution of 4.1G in Schwann cells. In developing mouse sciatic nerves, 4.1G was diffusely distributed in immature Schwann cells and gradually localized at paranodes, incisures, and periaxonal and mesaxonal membranes during their maturation. These data support the concept that 4.1 G plays an important role in the membrane expansion and specialization that occurs during formation and maintenance of myelin internodes in the peripheral nervous system. (c) 2006 Wiley-Liss, Inc.