Transcription factors are crucial in both directing and responding to developmental cues during organogenesis. The GATA family of zinc finger transcription factors are critical regulators of cell lineage specific gene expression and development. Previous studies from our laboratory have demonstrated that GATA6 regulates several aspects of lung development and gene expression including airway epithelial cell differentiation, surfactant protein expression, and branching morphogenesis. Transgenic inhibition of GATA6 activity in mice results in decreased SP-B and SP-C expression as well as decreased alveolar type 1 cell differentiation. Lungs from these mice also display dilated distal airspaces, due to decreased branching morphogenesis. Moreover, we have demonstrated that GATA6 binds to Nkx2.1 and synergistically regulates lung specific gene expression. Similarities between the down-stream targets of Nkx2.1 and GATA6 (i.e. SP-B and SP-C) have lead us to hypothesize that regulation of lung epithelial gene transcription by GATA6 occurs, at least in part, through protein-protein interactions with other transcriptional regulators, including Nkx2.1. Together, these protein-protein interactions likely regulate specific target genes in the lung epithelium that are important for cell differentiation and development, in a temporal specific manner. To characterize the importance of GATA6-Nkx2.1 interactions and the temporal requirement of GATA6 expression during lung development, we propose to 1) Define the functional interaction between GATA6 and Nkx2.1 on target promoters and during lung development, 2) Define the minimal peptide sequence in GATA6 that mediates GATA6 and Nkx2.1 interactions and determine its importance in vitro, and 3) Determine the temporal requirement of GATA6 in the lung epithelium using a floxed GATA6 allele and a temporally inducible transgenic cre mouse line.
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