TTF-1 Phosphorylation Is Required for Peripheral Lung Morphogenesis, Perinatal Survival, and Tissue-specific Gene Expression

Abstract

Thyroid transcription factor-1 (TTF-1) is a 43-kDa, phosphorylated member of the Nkx2 family of homeodomain-containing proteins expressed selectively in lung, thyroid, and the central nervous system. To assess the role of TTF-1 and its phosphorylation during lung morphogenesis, mice bearing a mutant allele, in which seven serine phosphorylation sites were mutated, Titf1 PM/PM , were generated by homologous recombination. Although heterozygous Titf1 PM/؉ mice were unaffected, homozygous Titf1 PM/PM mice died immediately following birth. In contrast to Titf1 null mutant mice, which lack peripheral lung tissues, bronchiolar and peripheral acinar components of the lung were present in the Titf1 PM/PM mice. Although lobulation and early branching morphogenesis were maintained in the mutant mice, abnormalities in acinar tubules and pulmonary hypoplasia indicated defects in lung morphogenesis later in development. Although TTF-1 PM protein was readily detected within the nuclei of pulmonary epithelial cells at sites and abundance consistent with that of endogenous TTF-1, expression of a number of known TTF-1 target genes, including surfactant proteins and secretoglobulin 1A, was variably decreased in the mutant mice. Vascular endothelial growth factor mRNA was decreased in association with decreased formation of peripheral pulmonary blood vessels. Genes mediating surfactant homeostasis, vasculogenesis, host defense, fluid homeostasis, and inflammation were highly represented among those regulated by TTF-1. Thus, in contrast to the null Titf1 mutation, the Titf1 PM/PM mutant substantially restored lung morphogenesis. Direct and indirect transcriptional targets of TTF-1 were identified that are likely to play important roles in lung formation and function.Lung formation begins with the outpouching of endodermal tissues from the laryngeal-tracheal-esophageal groove at embryonic day (E) 1 9 -9.5 in the mouse embryo. Epithelial lined tubules invade the splanchnic mesenchyme and undergo branching morphogenesis to form bronchi, bronchioles, and alveolar regions of the adult lung. Thyroid transcription factor-1 (genomic designation Titf1; also termed TEBP, or Nkx2

Nuclear Factor of Activated T Cells Regulates Transcription of the Surfactant Protein D Gene (Sftpd) via Direct Interaction with Thyroid Transcription Factor-1 in Lung Epithelial Cells

“…Consistent with this finding, alveolar epithelial type II cells that co-express TTF-1 and NFATc3 mRNA secrete SP-D protein in culture (48). The role of TTF-1 and its phosphorylation mediated by several kinases play a critical role in lung development (61,62). Thus, disparate signaling events that post-translationally influence TTF-1 and NFATc3 function may converge on target genes to initiate their spatial, temporal, and cell-specific expression.…”

Oncogenic cooperation and coamplification of developmental transcription factor genes in lung cancer

“…In contrast to the well publicized oncogene addiction model that invokes a tumorspecific gain-of-function event (33), lineage dependency relies on the deregulation of key developmental survival mechanisms to promote tumorigenesis. Interestingly, given its essential function in lung development (34,35) and restrictive expression in lung tissue (36), TTF1 was speculated to be an appealing candidate cell lineage-survival oncogene in lung cancer (32). Very recently, Tanaka et al (37) provided evidence that sustained TTF1 expression may be crucial for a subset of lung AC.…”

Compensatory Roles of Foxa1 and Foxa2 during Lung Morphogenesis

“…Foxa also modulates gene expression by interacting with other transcription factors, including SP1, the CCAAT/enhancer-binding protein, and the retinoic acid receptor/retinoid X receptor (57)(58)(59). Foxa1 and Foxa2 are co-expressed with TF1 and share transcriptional targets in the respiratory epithelium (54,60). It is therefore likely that other transcription factors interact and cooperate with Foxa1 and Foxa2 in a complex transcriptional program that regulates gene expression in the developing lung.…”