The transcription factor GATA6 is essential for branching morphogenesis and epithelial cell differentiation during fetal pulmonary development

Recent loss-of-function studies in mice show that the transcription factor GATA6 is important for visceral endoderm differentiation. It is also expres sed in early bronchial epithelium and the observation that this tissue does not receive ang contribution from Gata6 double mutant embryonic stem (ES) cells in chimeric mice suggests that GATA6 may play a crucial role in lung development. The aim of this study was to determine the role of GATA6 in fe tal pulmonary development. We show that Gata6 mRNA is expressed predominant ly in the developing pulmonary endoderm and epithelium, but at E15.5 also i n the pulmonary mesenchyme. Blocking or depleting GATA6 function results in diminished branching morphogenesis both in vitro and in vivo. TTF1 express ion is unaltered in chimeric lungs whereas SPC and CC10 expression are atte nuated in abnormally branched areas of chimeric lungs. Chimeras generated i n a ROSA26 background show that endodermal cells in these abnormally branch ed areas are derived from Gata6 mutant ES cells, implicating that the defec t is intrinsic to the endoderm, Taken together, these data demonstrate that GATA6 is not essential for endoderm specification, but is required for nor mal branching morphogenesis and late epithelial cell differentiation.