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Axonal Regulation of Myelin Myelinating Schwann Cells Protein The Journal of Neuroscience, September 1988, 8(9): 35153521 Axonal Regulation of Myelin Protein mRNA Levels Actively Myelinating Schwann Cells Bruce D. Trapp, Peter Hauer, and Greg Lemkel The Johns Hopkins University School of Medicine, Department of Neurology, Neuromuscular Division, Baltimore, Maryland 21205, and ‘Molecular Neurobiology Laboratory, The Salk Institute, San Diego, California 92138 Upon transection of a peripheral nerve, axons distal to the the major myelin proteins are dramatically reduced (Mirsky et transection degenerate. As a consequence of this axonal al., 1980; Politis et al., 1982; Poduslo et al., 1984; Willison et degeneration, myelin-forming Schwann cells cease biosyn- al., 1988). These and related data have been interpreted as thesis of new myelin membrane, contribute to phagocytosis indicating that axons induce and regulate myelin gene expres- of previously formed myelin, and markedly down-regulate sion during formation and maintenance of the myelin sheath. expression of myelin-specific markers. Among the most We have tested this hypothesis directly. Rat sciatic nerves prominent of these down-regulated markers are the major were transected during a period of active myelination, and the structural proteins of peripheral myelin, P, and myelin basic level and distribution of P, and MBP mRNAs were determined protein (MBP). We have used slot blot and in situ hybridiza- in denervated regions distal to the site of transection. We find tion techniques to demonstrate that for actively myelinating a 40-fold decreasein the level of these messagesat 5 d post- Schwann cells, down-regulation of the P, and MBP genes transection. In situ hybridization studies demonstrate that this occurs primarily at the level of mRNA expression. Together decreaseoccurs simultaneously along the entire distal stump. with other recent data, these findings strongly argue for ax- These data indicate that axons regulate myelination at the level onal modulation of P, and MBP gene transcription during of Schwann cell mRNA expression, most probably through di- active myelination. rect modulation of transcription. Schwann cells of the PNS can be divided into 2 distinct cell Materials and Methods types, those that ensheathemultiple axons and those that tightly Tissues. Sixteen35d-old Sprague-Dawley rats were used for morpho- and repeatedly wrap a singleaxon, resulting in formation of the logical studies. Under appropriate anesthetic, the right sciatic nerve was transected above the sciatic notch in 8 of the rats. The proximal stump myelin sheath (Raine, 1984; Webster and Favilla, 1984). Al- and attached L4 and L5 roots were removed to prevent reinnervation though all Schwann cells have the potential to form this sheath, of the distal stump which remained in its normal orientation so that they will do so only upon induction by appropriate peripheral various regions could be analyzed. At 2, 5, 10, and 20 d posttransection, axons (Aguayo et al., 1976; Weinberg and Spencer, 1976; Bray 2 normal rats and 2 rats having right sciatic nerve transections were et al., 1981). A key feature of this axon-mediated induction is perfused with 4% paraformaldehyde in 0.08 M phosphate buffer. The distal stumps and the left sciatic nerves were removed from transected the activation and high-level expressionof the genesencoding animals, and the right sciatic nerve was removed from control animals. the major myelin proteins P, and myelin basic protein (MBP) These nerves were dissected into 3 equal segments (proximal, mid, and (Lemke, 1986). distal), placed in fixative overnight and then processed to paraffin by P, and MBP accumulate to very high levels during postnatal standard procedures. Two paraffin blocks were produced for each time point. Both contained the transected distal stump, the untransected left development, with a time coursethat closely parallels the rate sciatic nerve, and the right sciatic nerve from a control animal. Sections of myelin production in peripheral nerve (Wood and Engel, were cut at a thickness of 6 pm, placed on glass slides, deparaffinized, 1976; Lemke and Axel, 1985; Willison et al., 1987). Schwann and rehydrated prior to use. In situ hybridization and immunohisto- cells that do not elaborate myelin, however, do not express chemistry were performed separately on adjacently cut sections. significant amounts ofthese proteins (Brockeset al., 1979;Trapp Fifty 35-d-old Sprague-Dawley rats were used for biochemical studies. Under appropriate anesthetic, both sciatic nerves were transected above et al., 1981, 1987; Willison et al., 1988). Previous studieshave the sciatic notch in 25 of the animals. The proximal end of each distal also indicated that maintenance of the myelin sheath depends stump was sutured into the musculature at the inferior aspect of the on survival of myelinated axons. When myelinated axons de- thigh. At 1, 2, 5, 10, and 20 d after transection, the distal stumps from generate, for example, both myelin synthesisand expressionof 5 animals and the sciatic nerves from 5 control animals were removed and stored in liquid nitrogen prior to RNA isolation. In situ hybridization. Sections on slides were prehybridized and hy- bridized as described previously (Trapp et al., 1987). Probes were Received Dec. 10, 1987; revised Jan. 29, 1988; accepted Feb. 2, 1988. YS-labeled nick-translated PO and MBP cDNAs. Autoradiography was We thank Dr. John Griffin for critical review of the manuscriot. Cindi Cootauco performed by standard procedures. Following development of the emul- for technical assistance, and Rod Graham for typing and edit& the manuscript. sion, sections were stained with hematoxylin, dehydrated, and overlaid This work was supported by Grants NS 22849 (B.D.T.) and NS 23896 (G.L.) from the NIH and Grant RG 1844 (G.L.) from the National Multiple Sclerosis Society. with coverslips. Sections were photographed witha Zeiss Axiophat mi- B.D.T. is a Harry Weaver Nemosciences Scholar of the National Multipie croscone under both bright and dark fields. The P, and MBP cDNA Sclerosis Society; G.L. is an awardee of the Pew Scholars Program in the Biomed- clones-used have been characterized and described elsewhere (Roach et ical Sciences. al., 1983; Lemke and Axel, 1985). Correspondence should be addressed to Bruce D. Trapp, The Johns Hopkins Zmmunohistochemistry. Sections were stained with a well-character- University School of Medicine, 600 North Wolfe Street, Meyer 6- 18 1, Baltimore, ized P, antiserum(Trapp et al., 1979) by the peroxidase-antiperoxidase MD 21205. procedure as described previously (Trapp et al., 1981). Copyright 0 1988 Society for Neuroscience 0270-6474/88/093515-07$02.00/O RNA isolation and analysis. Total RNA was extracted from frozen 3516 Trapp et al. - Axons Regulate Myelin mRNA Levels I PO mRNA MBP mRNA c T 1 c T 2- 5 0 10 20 3b DAYS POST TRANSECTION DAYS POST TRANSECTION Figure 1. Slot blot determination of major myelin RNA levels in control and transected rat sciatic nerves. Total cellular RNA (1 pg) from control (C) or transected (7’) rat sciatic nerves and from rat liver (L) was immobilized to a nylon support and hybridized at high stringency to 32P-radiolabeled P, (left) and MBP (right) cDNA clones. Numbers on blots refer to days posttransection; a day 10 posttransection control point was not taken. Exposure time for the PO blot was 12 hr with an intensifying screen; for the MBP blot, 24 hr with an intensifying screen. Each blot autoradiogram was scanned with a densitometer, and percentage control values were calculated by dividing the integrated hybridization signal from each experimental (transected) point by the average of the hybridization signal for the 4 control points. Autoradiography was performed at -70°C using preflashed X-ray film. tissue by homogenization in guanidine thiocyanate and subsequent pre- and immobilized to GeneScreen (New England Nuclear) using a slot cipitation with lithium chloride as described by Cathala et al. (1983). blotter (Schleicher and Schuell). Slot blots were hybridized and washed Then, 0.4, 1, and 2 fig of total RNA from transected and control sciatic at high stringency using nick-translated 32P-labeled cDNA (P, and MBP) nerves and from liver were denatured in 6 x SSC/7.4% formaldehyde probes as described previously (Lemke and Axel, 1985). Figure 2. Comparison of the distribution of P, mRNA in longitudinally oriented parathn sections of aged-matched control (A, C, E) and 2 (B), 5 (O), and 20 d Q transected rat sciatic nerves. Clusters of P, mRNA were readily detectable in all control sections. The general distribution of PO mRNA 2 d after transection was similar to controls. P, mRNA clusters were reduced dramatically 5 d after transection and were not detected in 20 d transected nerves. Dark-field optics. Scale bar, 75 pm. The Journal of Neuroscience, September 1988, 8(9) 3517 Figure 3. Bright-field analysis of sections in Figure 2. Clusters of silver grains representing PO mRNA were concentrated around Schwann cell nuclei in control sections (A, C, E). Smaller P, mRNA clusters containing few silver grains surrounded Schwann cell nuclei 2 d after transection (B). Perinuclear concentrations of P, mRNA were rarely found 5 d after transcription (0, arrowhead)and were not detected in sections from 20 d posttransected nerves (F). A dramatic increase in the number of cell nuclei per unit area of nerve occurred between 5 and 20 d after transection. Scale bar, 30 pm. tribution of PO and MBP mRNAs in tissuesections of 2, 5, 10, Results and 20 d transected distal stumps and compared this distribu- Myelin RNA levels in transectedsciatic nerves tion to that found in age-matchedcontrol nerves. For each time We extracted total cellular RNA from normal sciatic nerves and point, sectionsof control and transected nerves were hybridized from the distal stumps of transected nerves at 1, 2, 5, 10, and on the sameslide. The relative intensities of hybridization sig- 20 d posttransection. The relative levels of PO and MBP tran- nals in normal and transected nerves were thereby internally scripts present in each of these RNA preparations were then controlled.
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