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Department of Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60607-7170
Development of the mouse lung initiates on day 9.5 postcoitum from the laryngotracheal groove and involves
mesenchymal-epithelial interactions, in particular, those between the
splanchnic mesoderm and epithelial cells (derived from foregut
endoderm) that induce cellular proliferation, migration, and
differentiation, resulting in branching morphogenesis. This
developmental process mediates formation of the pulmonary bronchiole
tree and integrates a terminal alveolar region with an extensive
endothelial capillary bed, which facilitates efficient gas exchange
with the circulatory system. The major function of the
mesenchymal-epithelial signaling is to potentiate the activity or
expression of cell type-specific transcription factors in the
developing lung, which, in turn, cooperatively bind to distinct
promoter regions and activate target gene expression. In this review,
we focus on the role of transcription factors in lung morphogenesis and
the maintenance of differentiated gene expression. These lung
transcription factors include forkhead box A2 [also known as
hepatocyte nuclear factor (HNF)-3
], HNF-3/forkhead homolog (HFH)-8
[also known as FoxF1 or forkhead-related activator-1], HNF-3/forkhead
homolog-4 (also known as FoxJ1), thyroid transcription factor-1
(Nkx2.1), and homeodomain box A5 transcription factors, the zinc finger
Gli (mouse homologs of the Drosophila cubitus interruptus)
and GATA transcription factors, and the basic helix-loop-helix Pod1
transcription factor. We summarize the phenotypes of transgenic and
knockout mouse models, which define important functions of these
transcription factors in cellular differentiation and lung branching morphogenesis.
winged helix/forkhead box deoxyribonucleic acid binding domain; hepatocyte nuclear factor-3/forkhead homolog; homeodomain box; Nkx2.1; GATA; Gli; Pod1
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