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Advisor: Patrizia Casaccia-Bonnefil, MD, PhD
Graduate Program in Molecular Genetics, Microbiology and Immunology
Thursday, April 24, 2008
Myelination of the axons is essential for quick saltatory axonal conduction. In the central nervous system (CNS) myelination is carried out by oligodendrocytes and in the peripheral nervous system (PNS) by Schwann cells. Previous studies in our laboratory have shown that deacetylation of nucleosomal histones by HDACs is a necessary step for oligodendrocyte differentiation. Screening of the promoters of HDAC-regulated genes revealed the presence of transcription factor Yin Yang1 (YY1) binding motif on 25% of the promoters examined. Conditional deletion of yy1 in oligodendrocytes and Schwann cells in mouse was achieved by Cre-loxP strategy. The yy1 cko mice developed tremor and ataxia in the second postnatal weeks and progressively deteriorated. EM studies revealed severe hypomyelination in the CNS, characterized by decreased number of myelinated axons and decreased myelin sheath thickness. This was caused by the persistence of oligodendrocyte progenitor at an immature stage. In addition, in vitro ablation of YY1 in nestin + neural precursor cells similarly impaired the differentiation along the oligodendrocyte lineage in a cell type-specific manner. At the molecular level, this impairment is associated with persistent histone acetylation and high levels of transcriptional inhibitors ( Tcf4 and Id4 ) of myelin gene products.
In yy1 cko mice, tail paralysis and abnormal hindlimb posture reflex were also observed, suggesting defective myelination in the PNS. Indeed, hypomyelination in the PNS was confirmed by immunohistochemistry and EM. Ultrastructural study evidence indicated that yy1 -deficient Schwann cells were arrested at a pro-myelinating stage. The peripheral nerves of yy1 cko mice shared multiple features with Egr2 mutant mice including a similar clinical phenotype and the overlapping gene expression profiles. This suggested that YY1 and EGR2 shared similarly functions in PNS myelination.
Together, we identified YY1 as an important regulator of myelination in both CNS and PNS. However the mechanism of its function is different in distinct cell types. In oligodendrocyte YY1 is necessary for myelination by down regulating the transcriptional inhibitors of myelin genes, while in Schwann cell it acts through a master regulator (EGR2) of PNS myelination.