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Gata4 is necessary for normal pulmonary lobar development.

ABSTRACT: Mutations of Fog2 in mice result in a phenotype that includes pulmonary lobar defects. To determine whether formation of the accessory lobe bronchus is mediated by a Gata family cofactor, we evaluated embryonic lungs from mice carrying missense mutations that cause loss of FOG-GATA protein interaction. Lungs from embryos carrying a missense mutation in Gata6 were structurally normal, while lungs from embryos carrying mutations of either Gata4 or of both Gata4 and Gata6 had a structural phenotype that matched the Fog2 mutant phenotype. Expression analysis showed that Gata4 and Fog2 are expressed in the ventral and medial pulmonary mesenchyme during secondary budding. Although Gata4 has not previously been suspected as playing a role in lung development, we have found that a Fog2-Gata4 interaction is critical for the development of normal pulmonary lobar structure, and this phenotype is not influenced by the additional loss of Gata6 interaction. Fog2 and Gata4 in the early pulmonary mesenchyme participate in patterning the secondary bronchus of the accessory lobe.

SUBMITTER: Ackerman KG

PROVIDER: S-EPMC1899327 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Gata4 is necessary for normal pulmonary lobar development.

Ackerman Kate G KG Wang Jianlong J Luo Liqing L Fujiwara Yuko Y Orkin Stuart H SH Beier David R DR

American journal of respiratory cell and molecular biology 20061201 4

Mutations of Fog2 in mice result in a phenotype that includes pulmonary lobar defects. To determine whether formation of the accessory lobe bronchus is mediated by a Gata family cofactor, we evaluated embryonic lungs from mice carrying missense mutations that cause loss of FOG-GATA protein interaction. Lungs from embryos carrying a missense mutation in Gata6 were structurally normal, while lungs from embryos carrying mutations of either Gata4 or of both Gata4 and Gata6 had a structural phenotype ...[more]

PMID: 17142311

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Project description:The heart is the first functioning organ to develop during embryogenesis. The formation of the heart is a tightly regulated and complex process, and alterations to its development can result in congenital heart defects. Mutations in sarcomeric proteins, such as alpha myosin heavy chain and cardiac alpha actin, have now been associated with congenital heart defects in humans, often with atrial septal defects. However, cardiac troponin T (cTNT encoded by gene TNNT2) has not. Using gene-specific antisense oligonucleotides, we have investigated the role of cTNT in chick cardiogenesis. TNNT2 is expressed throughout heart development and in the postnatal heart. TNNT2-morpholino treatment resulted in abnormal atrial septal growth and a reduction in the number of trabeculae in the developing primitive ventricular chamber. External analysis revealed the development of diverticula from the ventricular myocardial wall which showed no evidence of fibrosis and still retained a myocardial phenotype. Sarcomeric assembly appeared normal in these treated hearts. In humans, congenital ventricular diverticulum is a rare condition, which has not yet been genetically associated. However, abnormal haemodynamics is known to cause structural defects in the heart. Further, structural defects, including atrial septal defects and congenital diverticula, have previously been associated with conduction anomalies. Therefore, to provide mechanistic insights into the effect that cTNT knockdown has on the developing heart, quantitative PCR was performed to determine the expression of the shear stress responsive gene NOS3 and the conduction gene TBX3. Both genes were differentially expressed compared to controls. Therefore, a reduction in cTNT in the developing heart results in abnormal atrial septal formation and aberrant ventricular morphogenesis. We hypothesize that alterations to the haemodynamics, indicated by differential NOS3 expression, causes these abnormalities in growth in cTNT knockdown hearts. In addition, the muscular diverticula reported here suggest a novel role for mutations of structural sarcomeric proteins in the pathogenesis of congenital cardiac diverticula. From these studies, we suggest TNNT2 is a gene worthy of screening for those with a congenital heart defect, particularly atrial septal defects and ventricular diverticula.

Project description:BackgroundThe mainstay of assessment of the fetal lungs in clinical practice is via evaluation of pulmonary size, primarily using 2D ultrasound and more recently with anatomical magnetic resonance imaging. The emergence of advanced magnetic resonance techniques such as T2* relaxometry in combination with the latest motion correction post-processing tools now facilitates assessment of the metabolic activity or perfusion of fetal pulmonary tissue in vivo.ObjectiveThis study aimed to characterize normal pulmonary development using T2* relaxometry, accounting for fetal motion across gestation.MethodsDatasets from women with uncomplicated pregnancies that delivered at term, were analyzed. All subjects had undergone T2-weighted imaging and T2* relaxometry on a Phillips 3T magnetic resonance imaging system antenatally. T2* relaxometry of the fetal thorax was performed using a gradient echo single-shot echo planar imaging sequence. Following correction for fetal motion using slice-to-volume reconstruction, T2* maps were generated using in-house pipelines. Lungs were manually segmented and mean T2* values calculated for the right and left lungs individually, and for both lungs combined. Lung volumes were generated from the segmented images, and the right and left lungs, as well as both lungs combined were assessed.ResultsEighty-seven datasets were suitable for analysis. The mean gestation at scan was 29.9±4.3 weeks (range: 20.6-38.3) and mean gestation at delivery was 40±1.2 weeks (range: 37.1-42.4). Mean T2* values of the lungs increased over gestation for right and left lungs individually and for both lungs assessed together (P=.003; P=.04; P=.003, respectively). Right, left, and total lung volumes were also strongly correlated with increasing gestational age (P<.001 in all cases).ConclusionThis large study assessed developing lungs using T2* imaging across a wide gestational age range. Mean T2* values increased with gestational age, which may reflect increasing perfusion and metabolic requirements and alterations in tissue composition as gestation advances. In the future, evaluation of findings in fetuses with conditions known to be associated with pulmonary morbidity may lead to enhanced prognostication antenatally, consequently improving counseling and perinatal care planning.

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Gata4 is necessary for normal pulmonary lobar development.

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Gata4 is necessary for normal pulmonary lobar development.

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