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senchymal stem cells to express Schwann cell markers. We could show that this time period is sufficient to monitor SREBP target gene activation. The up regulation of lipogenic genes like NSDHL, LDLR and HMGCR recapitulates the developmental process monitored during in vivo Schwann cell maturation and has been shown in rats and mice. During post-natal development glial cells of the peripheral nervous system start to ensheath axons and hence, need to synthesize large amounts of myelin. In protein lysates from sciatic nerves of new born mice strong S6 activation was shown, correlating with the time point of strongest myelin synthesis. 71% of the myelin membrane is composed of lipids and one of the most abundant form of lipids in the membrane is cholesterol. Sterol regulatory elementbinding protein, a protein necessary for SREBP processing, has been shown to be required for the myelination process, since its loss resulted in hypomyelination and abnormal gait. Therefore, the induction of lipogenic genes can be considered a hallmark of functional Schwann cell development. We showed that during differentiation of AFS cells Vorapaxar cost ribosomal protein S6 was phosphorylated and that this activation correlated with expression of NGFR, a prototype early Schwann cell marker. On the contrary, inhibition of S6 phosphorylation by rapamycin led to a decrease in Schwann cell marker expression, a reduction in free cholesterol accumulation and a down regulation of SREBP target marker available, even in the presence of rapamycin. In contrast, the lipogenic markers LDLR and HMGCR were not rescued by the S6K1 mutant in the presence of rapamycin. We also overexpressed wild type S6K1 and detected a consistent increased expression of GFAP and NGFR, but not of nestin. A TOS motive mutated S6K1, which strongly inhibits S6 activation, was not able to increase S100b expression. This indicates that during AFS differentiation Schwann cell-specific S100b, GFAP and NGFR are positively regulated by mTORC1 through S6K1, whereas Early Schwann Cell Differentiation of Amniotic Fluid Stem Cells genes. Rapamycin treatment of mice resulted in a decrease of Schwann cell differentiation and lipogenic marker expression on the RNA level in sciatic nerves in vivo. We could not detect changes in myelin composition of everolimus treated versus untreated sciatic nerves probably because myelination is already completed 7 weeks after birth. It was shown that myelin as well as overall protein translation is down regulated during maturation of peripheral nerves and that expression of the Mek1DD allel, which induces MAPK activation and also mTOR activation, can override the termination of myelin growth. In this model myelinisation proceeds until P90 and treatment with rapamycin from P17 to P30 strongly reduced myelin growth and axonal packing, when compared to vehicle treated controls. Since rapamycin treatment resulted in a suppression of SREBP target genes, which regulate both synthesis and uptake of cholesterol, we next blocked only cholesterol synthesis. Lovastatin was used to inhibit HMG-CoA reductase and, as expected, lipogenic marker genes were up regulated in response to the treatment, PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19674970 but surprisingly, also Schwann cell markers were enhanced. This suggests that lipid uptake, but not cholesterol synthesis is important for Schwann cell differentiation. Importantly, our results also suggest PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19674470 that for in vitro protocols, statins might promote differentiation of AFS cells or other stem cells into

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Author: nucleoside analogue