Normal Cells in Basal Laminas Dystrophic .-- Are Realized on Dystrophic Shiverer Chimera Nerves Schwann

Multiple discontinuities are observed in the basal laminas of Schwann cells in mature dystrophic mice. To explore the pathogenesis of this abnormality we have exploited a dystrophic ~-~ shiverer mouse chimera preparation in which both the basal lamina phenotype and the genotype of myelin-forming Schwann cells can be determined. If the basal lamina abnormality were to arise from an intrinsic deficiency of the dystrophic Schwann cell itself, only those Schwann cells of dystrophic genotype could express the mutant phenotype, whereas the coexisting population of shiverer Schwann cells should express'typically normal basal laminas. No such distinction was observed; rather both dystrophic and shiverer Schwann cells were found to express relatively normal basal laminas and two pathogenetic mechanisms remain theoretical possibilities. The dystrophic Schwann cell population may be intrinsically defective but also may be rescued by obtaining the normal product of the dy locus synthesized by the coexisting shiverer cells. Alternatively, an extra Schwann cell deficiency existing within dystrophic mice may be normalized by shiverer cells and the normal intrinsic potential of both dystrophic and shiverer Schwann cells can then be realized. Regardless of the exact mechanism underlying these findings, some extracellularly mediated influence, emanating in vivo from shiverer cells, is capable of ameliorating the basal lamina deficiency typically expressed by dystrophic Schwann cells. In the peripheral nervous system of mature dystrophic mice, two striking morphological abnormalities can be recognized. In certain spinal roots and cranial nerves, Schwann cells fail to separate and ensheath axons so that groups of closely apposed naked axons, normally seen only during early development, persist (1, 2). In the remainder of the dystrophic peripheral nervous system, relatively normal axon-Schwann cell relationships are achieved (3), but the basal laminas covering both myelinated and unmyelinated fibers have multiple small gaps (4). Both of these morphological abnormalities are phenotypic deficiencies specific to Schwann cells; the presence of naked axons results from a failure of the Schwann cell population to separate and ensheath the axons during primary development, and abnormal basal lamina has been observed only on the surface of Schwann cells. Various experimental manipulations of the peripheral nervous system in dystrophic mice have indicated that both of these "Schwann cell" deficiencies can be modified during regeneration (5, 6) and in tissue cultures (7, 8). Nevertheless, it is not yet known what cell type THE JOURNAL OF CELL BIOLOGY . VOLUME 99 NOVEMBER 1984 1831-1837 The Rockefeller University Press • 0021-952518411111831107 $1.00 or types are primarily responsible for the pathology observed in vivo. Although the in vitro experiments have indicated that endoneurial fibroblasts exert an important influence on the development of basal laminas by dystrophic Schwann cells, either the Schwann cell itself, a defect expressed exclusively by some extra Schwann cell type, or a more complex interaction between both Schwann cells and some extra glial element sharing the same intrinsic deficiency may be involved. In an attempt to dissect this pathogenetic sequence, we have examined the basal lamina expressed within the peripheral nerves of chimeras. If the basal lamina abnormalities on Schwann cells in dystrophic mice were entirely a consequence of an intrinsic defect expressed by the Schwann cell itself, we would predict that within these chimera nerves only those Schwann cells of dystrophic genotype could express patchy basal laminas. However, if some component extrinsic to the Schwann cell itself were involved in the pathogenesis of this basal lamina abnormality, no such direct correlation would be expected. 1831 on May 1, 2019 jcb.rupress. org Downloaded from http://doi.org/10.1083/jcb.99. 5.1831 Published Online: 1 November, 1984 | Supp Info: