Disease relevance of Foxf1a

• Inactivation of both Foxf2 alleles, or one allele each of Foxf1 and Foxf2, cause a range of defects, including megacolon, colorectal muscle hypoplasia and agangliosis [1].
• Decreased pulmonary expression of Forkhead Box f1 (Foxf1) transcription factor was associated with lethal alveolar hemorrhage in 55% of the Foxf1 +/- newborn mice [2].
• Foxf2, on the other hand, is more prominent than Foxf1 in mesenchyme around the oral cavity, as would be predicted from the cleft palate phenotype [3].

High impact information on Foxf1a

• Here, we show that targeting murine Foxf1 and Foxf2, encoding forkhead transcription factors, has pleiotropic effects on intestinal paracrine signaling [1].
• Foxf expression in the splanchnic mesoderm is activated by Indian and sonic hedgehog secreted by the epithelium [1].
• Extracellular matrix, particularly collagens, is severely reduced in Foxf mutant intestine, which causes epithelial depolarization and tissue disintegration [1].
• We found that regenerating Foxf1 +/- liver exhibited defective stellate cell activation following CCl(4) liver injury, which was associated with diminished induction of type I collagen, alpha-smooth muscle actin, and Notch-2 protein and resulted in severe hepatic apoptosis despite normal cellular proliferation rates [4].
• In conclusion, Foxf1 +/- mice exhibited abnormal liver repair, diminished activation of hepatic stellate cells, and increased pericentral hepatic apoptosis following CCl(4) injury [4].

Chemical compound and disease context of Foxf1a

• We demonstrated that adult foxf1(+/-) mice died from severe lung hemorrhage after butylated hydroxytoluene (BHT) lung injury and that this phenotype was associated with a 10-fold decrease in pulmonary Foxf1 expression and increased alveolar endothelial cell apoptosis that disrupted capillary integrity [5].

Biological context of Foxf1a

• In this study, we show that Foxf1 is expressed in hepatic stellate cells in developing and adult liver, suggesting that a subset of stellate cells originates from septum transversum mesenchyme during mouse embryonic development [4].
• Foxf1 +/- mice exhibit defective stellate cell activation and abnormal liver regeneration following CCl4 injury [4].
• We have disrupted Foxf1 and show that mutant embryos die at midgestation due to defects in mesodermal differentiation and cell adhesion [6].
• Expression of Foxf1 and the homeobox gene Irx3 defines the splanchnic and somatic mesodermal layers, respectively [6].
• Foxf1+/- gall bladders were significantly smaller and had severe structural abnormalities characterized by a deficient external smooth muscle cell layer, reduction in mesenchymal cell number, and in some cases, lack of a discernible biliary epithelial cell layer [7].

Anatomical context of Foxf1a

• Collectively, our data suggest that sustained expression of Foxf1 is essential for normal lung repair and endothelial cell survival in response to pulmonary cell injury [5].
• We demonstrate that FoxF2 is expressed in the mesenchyme adjacent to the epithelium in alimentary, respiratory, and urinary tracts, similar to FoxF1 (FREAC-1, HFH-8) [8].
• In a previous study, we showed that newborn foxf1(+/-) mice with diminished Foxf1 levels exhibited abnormal formation of pulmonary alveoli and capillaries and died postnatally [5].
• Previous studies have shown that haploinsufficiency of the splanchnic and septum transversum mesoderm Forkhead Box (Fox) f1 transcriptional factor caused defects in lung and gallbladder development and that Foxf1 heterozygous (+/-) mice exhibited defective lung repair in response to injury [4].
• The forkhead box f1 (Foxf1) transcription factor is expressed in the visceral (splanchnic) mesoderm, which is involved in mesenchymal-epithelial signaling required for development of organs derived from foregut endoderm such as lung, liver, gall bladder, and pancreas [7].

Associations of Foxf1a with chemical compounds

• Because liver regeneration requires a transient differentiation of stellate cells into myofibroblasts, which secrete type I collagen into the extracellular matrix, we examined Foxf1 +/- liver repair following carbon tetrachloride injury, a known model for stellate cell activation [4].
• Although BHT lung injury did not alter epithelial cell expression of HNF-3beta, a 65% reduction in HFH-8 mRNA levels was observed during the period of mesenchymal cell proliferation [9].

Regulatory relationships of Foxf1a

• HFH-8-expressing cells were colocalized with platelet endothelial cell adhesion molecule-1-positive alveolar endothelial cells and with alpha-smooth muscle actin-positive peribronchiolar smooth muscle cells [9].

Other interactions of Foxf1a

• A possible cause of this is misexpression of the cell-adhesion protein VCAM1 in Foxf1-deficient extra-embryonic mesoderm, which leads to co-expression of VCAM with its receptor, alpha(4)-integrin [6].
• In contrast, in newborn high-Foxf1(+/-) lungs, Notch-2 signaling was restored to the level found in wild-type mice, which was associated with normal microvascular formation and survival [10].
• Our previous studies demonstrated that haploinsufficiency of the Foxf1 gene caused pulmonary abnormalities with perinatal lethality from lung hemorrhage in a subset of Foxf1+/- newborn mice [7].

Analytical, diagnostic and therapeutic context of Foxf1a

• In situ hybridization studies demonstrated that the defective primary lung-bud development in early Foxf1(+/-) embryos was associated with fewer pulmonary mesenchymal-epithelial interfaces [11].

References