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The Tip60 chromatin remodeling complex is required for maintenance and polarity of Drosophila neural stem cells

dc.contributor.advisorWodarz, Andreas Prof. Dr.
dc.contributor.authorRust, Katja
dc.titleThe Tip60 chromatin remodeling complex is required for maintenance and polarity of Drosophila neural stem cellsde
dc.contributor.refereePieler, Tomas Prof. Dr.
dc.description.abstractengStem cells are self-renewing cells which produce differentiating offspring during development and tissue homeostasis. Appropriate regulation of stem cell division is highly important to ensure maintenance of the stem cell and prevent overproliferation and tumor formation. A widely used model in stem cell research is the Drosophila neural stem cell, which divides asymmetrically. Hereby, the underlying polarity network is highly conserved. In this study I investigate the role of Domino, the Drosophila homolog of mammalian p400, in Drosophila larval neural stem cells. Domino is the ATPase subunit of the Tip60 chromatin remodeling complex, which is conserved in eucaryotes. Like its homolog p400 and several members of the Tip60 complex, Domino has been implicated in the maintenance of stem cells in Drosophila and mammals. Several transcription factors have been described to interact with the Tip60 complex in mammalian stem cells, including the cell cycle regulator Myc. However, the exact mechanism of Tip60 complex function in stem cells and how the interaction with the various transcription factors regulates stem cell behaviour has not been fully unraveled. Knockdown studies of domino and other Tip60 members revealed that the Tip60 complex in a specific subunit composition is required to maintain Drosophila neural stem cells. Systematic analyses of potential Tip60 complex cofactors moreover reveal a role for Myc in Drosophila neural stem cell self-renewal. Subsequent investigations show that the Myc/Tip60 network ensures appropriate asymmetric neural stem cell division and prevents Prospero dependent premature differentiation. Using next generation sequencing I found that Domino regulates the expression of genes which regulate neuroblast fate. Further analyses reveal a role of the Tip60 complex in histone modification in Drosophila neural stem cells. Taken together, this suggests that as in mammals Myc recruits the Tip60 complex to target promoters for the regulation of gene expression. Remarkably, the proto-oncogene p53 and the p21 homolog Dacapo, a p53-responsive gene and cell cycle regulator, were found to be regulated by Domino. This points to the p53-pathway as a potential novel target of the Myc/Tip60 network in stem cells. The function of Myc and the Tip60 complex in Drosophila neural stem cells is remarkably similar to the role of the Myc/Tip60 pathway in mammalian pluripotent stem cells. Thus, the gene regulatory network for stem cell self-renewal in Drosophila is highly conserved. Therefore, this study contributes to the general understanding of how Myc and the Tip60 complex maintain the stem cell
dc.contributor.coRefereeShcherbata, Halyna PD Dr.
dc.subject.engNeural stem cellde
dc.subject.engCell polarityde
dc.affiliation.instituteGöttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)de
dc.subject.gokfullBiologie (PPN619462639)de

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