Defects in tracheoesophageal and lung morphogenesis inNkx2. 1 (−/−) mouse embryos

P Minoo, G Su, H Drum, P Bringas, S Kimura - Developmental biology, 1999 - Elsevier
P Minoo, G Su, H Drum, P Bringas, S Kimura
Developmental biology, 1999Elsevier
NKX2. 1 is a homeodomain transcriptional factor expressed in thyroid, lung, and parts of the
brain. We demonstrate that septation of the anterior foregut along the dorsoventral axis, into
distinct tracheal and esophageal structures, is blocked in mouse embryos carrying a
homozygous targeted disruption of theNkx2. 1locus. This is consistent with the loss ofNkx2.
1expression, which defines the dorsoventral boundary within the anterior foregut in wild-type
E9 embryos. Failure in septation between the trachea and the esophagus inNkx2. 1 (−/−) …
NKX2.1 is a homeodomain transcriptional factor expressed in thyroid, lung, and parts of the brain. We demonstrate that septation of the anterior foregut along the dorsoventral axis, into distinct tracheal and esophageal structures, is blocked in mouse embryos carrying a homozygous targeted disruption of theNkx2.1locus. This is consistent with the loss ofNkx2.1expression, which defines the dorsoventral boundary within the anterior foregut in wild-type E9 embryos. Failure in septation between the trachea and the esophagus inNkx2.1(−/−) mice leads to the formation of a common lumen that connects the pharynx to the stomach, serving both as trachea and as esophagus, similar in phenotype to a human pathologic condition termed tracheoesophageal fistula. The main-stem bronchi bifurcate from this common structure and connect to profoundly hypoplastic lungs. The mutant lungs fail to undergo normal branching embryogenesis, consist of highly dilated sacs that are not capable of sustaining normal gas exchange functions, and lead to immediate postnatal death.In situhybridization suggests reducedBmp-4expression in the mutant lung epithelium, providing a possible mechanistic clue for impaired branching. Functional deletion ofNkx2.1blocks pulmonary-specific epithelial cell differentiation marked by the absence of pulmonary surfactant protein gene expression. Altered expression of temporally regulated genes such asVegfdemonstrates that the lung inNkx2.1(−/−) mutant embryos is arrested at early pseudoglandular (E11–E15) stage. These results demonstrate a critical role forNkx2.1in morphogenesis of the anterior foregut and the lung as well as in differentiation of pulmonary epithelial cells.
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