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First published online December 12, 2006
doi: 10.1242/10.1242/dev.02720

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GATA and Nkx factors synergistically regulate tissue-specific gene expression and development in vivo

Yuzhen Zhang^1,*, Nibedita Rath^1,*, Sridhar Hannenhalli², Zhishan Wang¹, Thomas Cappola¹, Shioko Kimura³, Elena Atochina-Vasserman¹, Min Min Lu¹, Michael F. Beers¹ and Edward E. Morrisey^1,4,

¹ Department of Medicine and University of Pennsylvania, Philadelphia, PA 19104, USA.
² Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MA 20892, USA.
⁴ Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.

Author for correspondence (e-mail: emorrise{at}mail.med.upenn.edu)

Accepted 27 October 2006

In vitro studies have suggested that members of the GATA and Nkx transcription factor families physically interact, and synergistically activate pulmonary epithelial- and cardiac-gene promoters. However, the relevance of this synergy has not been demonstrated in vivo. We show that Gata6-Titf1 (Gata6-Nkx2.1) double heterozygous (G6-Nkx DH) embryos and mice have severe defects in pulmonary epithelial differentiation and distal airway development, as well as reduced phospholipid production. The defects in G6-Nkx DH embryos and mice are similar to those observed in human neonates with respiratory distress syndromes, including bronchopulmonary dysplasia, and differential gene expression analysis reveals essential developmental pathways requiring synergistic regulation by both Gata6 and Titf1 (Nkx2.1). These studies indicate that Gata6 and Nkx2.1 act in a synergistic manner to direct pulmonary epithelial differentiation and development in vivo, providing direct evidence that interactions between these two transcription factor families are crucial for the development of the tissues in which they are co-expressed.

Key words: GATA, Nkx, Transcription factor, Synergy, Lung, Mouse

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