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Item HDAC1 and HDAC2 Control the Specification of Neural Crest Cells into Peripheral Glia(Society for Neuroscience, 2014-04-23) Jacob, Claire; Lötscher, Pirmin; Engler, Stefanie; Baggiolini, Arianna; Tavares, Sandra Varum; Brügger, Valérie; John, Nessy; Büchmann-Møller, Stine; Snider, Paige L.; Conway, Simon J.; Yamaguchi, Teppei; Matthias, Patrick; Sommer, Lukas; Mantei, Ned; Suter, Ueli; Department of Pediatrics, School of MedicineSchwann cells, the myelinating glia of the peripheral nervous system (PNS), originate from multipotent neural crest cells that also give rise to other cells, including neurons, melanocytes, chondrocytes, and smooth muscle cells. The transcription factor Sox10 is required for peripheral glia specification. However, all neural crest cells express Sox10 and the mechanisms directing neural crest cells into a specific lineagearepoorlyunderstood.Weshowherethathistonedeacetylases1and2(HDAC1/2)areessentialforthespecificationofneuralcrest cells into Schwann cell precursors and satellite glia, which express the early determinants of their lineage myelin protein zero (P0) and/or fatty acid binding protein 7 (Fabp7). In neural crest cells, HDAC1/2 induced expression of the transcription factor Pax3 by binding and activating the Pax3 promoter. In turn, Pax3 was required to maintain high Sox10 levels and to trigger expression of Fabp7. In addition, HDAC1/2 were bound to the P0 promoter and activated P0 transcription. Consistently, in vivo genetic deletion of HDAC1/2 in mouse neuralcrestcellsledtostronglydecreasedSox10expression,nodetectablePax3,virtuallynosatelliteglia,andnoSchwanncellprecursors in dorsal root ganglia and peripheral nerves. Similarly, in vivo ablation of Pax3 in the mouse neural crest resulted in strongly reduced expression of Sox10 and Fabp7. Therefore, by controlling the expression of Pax3 and the concerted action of Pax3 and Sox10 on their target genes, HDAC1/2 direct the specification of neural crest cells into peripheral glia.Item A retinoic acid response element is present in the mouse cellular retinol binding protein I (mCRBPI) promoter.(EMBO Press, 1991-08) Smith, W C; Nakshatri, H; Leroy, P; Rees, J; Chambon, PGenomic and cDNA sequences for the mouse cellular retinol binding protein I (mCRBPI) are presented. A specific cis-acting element responsible for retinoic acid (RA) inducibility of the mCRBPI promoter was identified and characterized. Deletion mapping of a CRBPI promoter--chloramphenicol acetyltransferase reporter gene construct localized this element to a 259 bp restriction fragment located approximately 1 kb upstream from the transcription start-site. A sequence closely resembling the previously characterized RA response element (RARE) of the RA receptor beta 2 (RAR-beta 2) promoter, and consisting of a direct repeat of the motif 5'-GGTCA-3' separated by three nucleotides, was found within this restriction fragment. Mutation of these 5'-GGTCA-3' motifs to GGAGC and GGGGC abolished RA-inducible transcription whereas a mutation to a direct repeat of the GTTCA motif found in the RARE of the RAR-beta 2 promoter resulted in enhanced inducibility. Oligonucleotides containing the direct repeat of the GGTCA motif were able to confer RA-dependent transcriptional enhancement to the herpes simplex thymidine kinase promoter, as well as to bind directly all three retinoic acid receptors (RARs) alpha, beta and gamma, as determined by gel retardation/shift assays. The control of CRBPI gene transcription by RA-RAR complexes interacting with the RARE characterized here may correspond to a feedback mechanism important in regulating retinoid metabolism and action.