ABSTRACT
Recent loss-of-function studies in mice show that the transcription factor GATA6 is important for visceral endoderm differentiation. It is also expressed in early bronchial epithelium and the observation that this tissue does not receive any 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 fetal pulmonary development. We show that Gata6 mRNA is expressed predominantly in the developing pulmonary endoderm and epithelium, but at E15.5 also in the pulmonary mesenchyme. Blocking or depleting GATA6 function results in diminished branching morphogenesis both in vitro and in vivo. TTF1 expression is unaltered in chimeric lungs whereas SPC and CC10 expression are attenuated in abnormally branched areas of chimeric lungs. Chimeras generated in a ROSA26 background show that endodermal cells in these abnormally branched areas are derived from Gata6 mutant ES cells, implicating that the defect is intrinsic to the endoderm. Taken together, these data demonstrate that GATA6 is not essential for endoderm specification, but is required for normal branching morphogenesis and late epithelial cell differentiation.
Subject(s)
Cell Differentiation , DNA-Binding Proteins/metabolism , Epithelial Cells/cytology , Gene Expression Regulation, Developmental , Lung/embryology , Morphogenesis/genetics , Transcription Factors/metabolism , Uteroglobin , Animals , Biomarkers , Chimera/embryology , Chimera/genetics , Chimera/metabolism , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , Embryonic and Fetal Development/genetics , GATA6 Transcription Factor , Gene Deletion , Histocytochemistry , In Situ Hybridization , Lung/cytology , Lung/metabolism , Mice , Mice, Knockout , Nuclear Proteins/analysis , Oligonucleotides, Antisense/genetics , Proteins/analysis , Proteins/genetics , Proteins/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Untranslated , Stem Cells/metabolism , Thyroid Nuclear Factor 1 , Transcription Factors/analysis , Transcription Factors/biosynthesis , Transcription Factors/deficiency , Transcription Factors/geneticsABSTRACT
Antenatal hormonal modulation of pulmonary growth has been successfully introduced in clinical practice to reduce the incidence of respiratory distress syndrome (RDS) of preterm born infants. However, a certain amount of reserve to repeat courses should be taken into account because of possible adverse effects of antenatal administration of glucocorticoids. Although in experimental animals thyroid hormones given alone were not shown to have stimulatory effects on pulmonary development, there was an apparent synergistic effect with corticosteroids. Yet, such effects have not been substantiated in clinical trials. Whereas in cases of congenital diaphragmatic hernia (CDH) in utero tracheal occlusion could stimulate fetal lung growth and modulation, the enhancement of type II cell differentiation is more likely to be achieved with antenatal exposure to hormonal therapies. However, there is still no firm scientific basis for either of these two treatment modalities in CDH. Yet, antenatal hormonal modulation is now soon to be tested in an extensive multi-center clinical trial. In this review, the current status of antenatal hormonal modulation of pulmonary growth will be described and its potential role in the treatment of CDH will be discussed.
Subject(s)
Hernia, Diaphragmatic/drug therapy , Hernias, Diaphragmatic, Congenital , Hormones/physiology , Lung/embryology , Adrenal Cortex Hormones/physiology , Animals , Clinical Trials as Topic , Female , Fetal Organ Maturity , Hernia, Diaphragmatic/physiopathology , Hormones/therapeutic use , Humans , Infant, Newborn , Lung/metabolism , Pregnancy , Respiratory Distress Syndrome, Newborn/prevention & control , Thyroid Hormones/physiologyABSTRACT
The hedgehog signalling pathway has been implicated in many different processes in fly and vertebrate development. It is now known that the hedgehog cascade is crucial for the patterning of the early respiratory system. Hedgehog signalling in the lung involves Gli transcription proteins, but their potential downstream target genes have yet to be identified. Bmp4 and Fgf10 have been shown to regulate lung branching morphogenesis but seem not to be targets of hedgehog signalling.
