Gastrulation is the process by which the three germ layers are generated during vertebrate development. Nodal ligands, which form a subgroup of the Transforming Growth Factor β (TGFβ) superfamily, regulate the expression several transcription factors implicated in gastrulation. Among these are the paired-like homeodomain transcription factors Goosecoid (Gsc) and Mixl1. At the molecular level, Gsc has been described to function as a transcriptional repressor by directly binding to paired homedomain binding sites on target promoters. Here, I describe a novel mechanism of transcriptional repression by Gsc. Using a molecular and embryological approach, I demonstrate that the forkhead transcription factor Foxh1, a major transducer of Nodal signaling, associates with Gsc which in turn recruits histone deacetylases to negatively regulate Mixl1 expression during early mouse development. Post-translational modification of transcription factors by SUMO proteins represents an important mechanism through which their activity is controlled. Here, I also demonstrate that Gsc is sumoylated in mammalian cells by members of the PIAS family of proteins and this modification potentiates the repressive activity of Gsc on direct targets such as the Xbra and Gsc promoters, but not on indirect targets such as Mixl1. Taken together, work presented in this thesis describes two novel mechanisms of transcriptional repression by Gsc.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/11214 |
| Date | 31 July 2008 |
| Creators | Izzi, Luisa |
| Contributors | Attisano, Liliana |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
| Format | 3904382 bytes, application/pdf |
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