The Role of Tgif1 and Tgif2 during Early Mouse Development
Taniguchi, Kenichiro, Department of Cell Biology, University of Virginia
Wontton, Dave, Department of Cell Biology, University of Virginia
Dwyer, Noelle, Department of Cell Biology, University of Virginia
Liu, Jeh-Ping, Department of Neuroscience, University of Virginia
Sutherland, Ann, Department of Cell Biology, University of Virginia
Tgif1 and its paralog Tgif2 are TALE homeodomain-containing transcription factors that function as transcriptional co-repressors. Tgif1 and Tgif2 interact with Smad2 and Smad3 to repress TGF/Nodal-activated transcription by recruiting general corepressors to Smad target genes. In humans, mutations at the TGIF1 locus are associated with holoprosencephaly (HPE), a prevalent disorder affecting forebrain and craniofacial development. The goal of this work is to determine the role of Tgif1 and Tgif2 during early mouse development and in the pathogenesis of HPE. From the analysis of Tgif1;Tgif2 double null embryos, we identified an in vivo role of Tgif1 and Tgif2 in regulating gastrulation and in limiting the level of Nodal signaling. We also showed an important role of Tgif1 and Tgif2 in regulating left-right asymmetry, and in the anterior development. We identified that Tgif function plays a role in HPE pathogenesis by regulating Shh signaling. Finally, we demonstrated that Tgif1 and Tgif2 regulate neuroepithelial cell polarity and the formation of primary cilia, a key mediator of the Shh signaling pathway, and demonstrate that Tgif-mediated repression of Nodal signaling is critical in regulating these processes. These studies demonstrate that Tgif1 and Tgif2 regulate Nodal signaling in vivo, and are critical regulators of Shh signaling and neuroepithelial cell polarity in a Nodal dependent manner.
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PHD (Doctor of Philosophy)
English
All rights reserved (no additional license for public reuse)
2012/08/01