Regulations of Development by Tgifs

TGIF and its paralog TGIF2 are TALE class homeodomain transcription factors that function as transcriptional repressors. The TGIFs can bind DNA at a TG-rich consensus site to actively repress transcription of target genes. TGIF and TGIF2 interact with Smad2 and Smad3 to repress TGF-activated transcription via the recruitment of general corepressors to Smad target genes. In humans, mutations at the TGIF locus are associated with craniofacial malformations in the developmental disorder Holoprosencephaly (HPE), indicating a role for TGIF in neural patterning. The goal of this work is to determine the roles of TGIF and TGIF2 in vivo. Through a combination of in vitro and in vivo assays we show that TGIF represses retinoid responsive target gene transcription through the recruitment of general corepressors to RXR-containing nuclear receptor complexes. Using a Tgif1 knockout mouse model, we show that loss of Tgif1 function sensitizes mice to changes in retinoic acid levels during anterior neural patterning. We perform a functional analysis of TGIF mutants associated with HPE and show that DNA binding and protein-protein interactions via the homeodomain are critical for the regulation of TGF-activated and retinoid responsive transcription by TGIF. We demonstrate that Tgif2 expression is up-regulated in the absence of Tgif1 during early development. Through the creation of a Tgif2 null mouse, we show that loss of Tgif2 function in the mouse results in growth defects and perinatal lethality that are enhanced by the loss of Tgif1 function on a pure strain background. By generating a Tgif1;Tgif2 double null mouse, we demonstrate that Tgif function within the Nodal signaling pathway is essential during gastrulation. These studies demonstrate that Tgifs are critical regulators of retinoic acid and TGF signaling at distinct times during development.

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