The present study focuses on the biological functions of the transcription factor EMA/E2F-6, a member of the E2F-family of transcription factors that play an import role in cell cycle progression, differentiation and apoptosis. EMA/E2F-6 functions as a transcriptional repressor by recruiting a large protein complex, that includes polycomb group proteins, to specific target genes in order to silence their expression. To identify the biological functions of EMA/E2F-6 mice lacking this factor were developed and subsequently analysed. EMA/E2F6-/- mice are born with the expected frequency, are fertile and develop normally up to 18 months of age. Then about 25 % of these mice develop a paralysis of the hind limbs and present with a severe primary myelination defect of the spinal cord (and in part of peripheral nerves, too) that is accompanied by a massive infiltration of macrophages. Importantly, the histological findings were also detected in EMA/E2F-6-/- mice lacking clinical symptoms albeit to a lesser extend. With respect to EMA/E2F-6 association with polycomb group (Pc-G) proteins there were no significant findings such as skeletal transformations. In addition, only a mild proliferation defect of T-lymphocytes was observed that, in a more severe form, is typical for Pc-G mutations in the mice. Surprisingly, embryonic fibroblasts from EMA/E2F-6-/- mice have no obvious cell cycle defects. Accordingly, gene expression profiles showed that classical E2F target genes were normally regulated in these cells. However, EMA/E2F-6-/- fibroblasts ubiquitously express genes like alpha-tubulin-3 and -7 that are normally expressed in a strictly testis-specific manner. All EMA/E2F-6-dependent target genes identified contain a conserved E2F-binding site in their promoters that is required both for EMA/E2F-6 binding and regulation.
| Identifer | oai:union.ndltd.org:HUMBOLT/oai:edoc.hu-berlin.de:18452/16045 |
| Date | 12 December 2005 |
| Creators | Pohlers, Michael |
| Contributors | Hagemeier, Christian, Saumweber, Harald, Daniel, Peter |
| Publisher | Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I |
| Source Sets | Humboldt University of Berlin |
| Language | German |
| Detected Language | English |
| Type | doctoralThesis, doc-type:doctoralThesis |
| Format | application/pdf |
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