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Foxf1 haploinsufficiency reduces Notch-2 signaling during mouse lung development
Vladimir V Kalinichenko1, Galina A Gusarova, Il-Man Kim
1Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois, Chicago, IL 60607-7170, USA. vkalin@uic.edu
American Journal of Physiology. Lung Cellular and Molecular Physiology
|November 11, 2003
Summary
Forkhead box f1 (Foxf1) transcription factor deficiency in mice causes lung microvascular defects and hemorrhage. Restoring Foxf1 levels rescues these defects, highlighting its critical role in lung development.
Area of Science:
- Developmental biology
- Molecular genetics
- Respiratory medicine
Background:
- The forkhead box (Fox) f1 transcription factor is crucial for embryonic development of multiple organs, including the lungs.
- Foxf1 haploinsufficiency in mice leads to pulmonary defects, but the underlying molecular mechanisms are not fully understood.
Purpose of the Study:
- To investigate the role of Foxf1 in regulating gene expression during lung development.
- To identify genes and signaling pathways affected by Foxf1 haploinsufficiency in the developing lung.
Main Methods:
- Gene expression analysis using Affymetrix microarrays in embryonic Foxf1(+/-) mouse lungs.
- Quantitative assessment of Notch-2 signaling components and microvascular development in Foxf1(+/-) mice at different developmental stages.
Main Results:
- Foxf1 haploinsufficiency in embryonic lungs diminished expression of key genes, including c-Met, SP-3, BMI-1, and cell cycle inhibitors.
- Notch-2 signaling was significantly reduced in Foxf1(+/-) lungs, with severity correlating to Foxf1 mRNA levels.
- Restoration of Foxf1 levels in high-Foxf1(+/-) mice normalized Notch-2 signaling, microvascular development, and survival.
Conclusions:
- Foxf1 regulates pulmonary expression of genes within the Notch-2 signaling pathway.
- Disruption of Notch-2 signaling due to Foxf1 haploinsufficiency leads to abnormal lung microvascular development and lethality.
- Foxf1 is essential for maintaining lung microvascular integrity and survival through Notch-2 pathway regulation.