The fetoprotein transcription factor (FTF) gene is essential to embryogenesis and cholesterol homeostasis and is regulated by a DR4 element.
The fetoprotein transcription factor (FTF) gene was inactivated in the mouse, with a lacZ gene inserted inframe into exon 4. LacZ staining of FTF+/- embryos shows that the mFTF gene is activated at initial stages of zygotic transcription. FTF gene activity is ubiquitous at the morula and blastocyst stages and then follows expression patterns indicative of multiple FTF functions in fetal development. FTF-/- embryos die at E6.5-7.5, with features typical of visceral endoderm dysfunction. Adult FTF+/- mice are hypocholesterolemic, and express liver FTF at about 40% of the normal level. Overexpression of liver FTF in transgenic mice indicates in vivo that FTF is an activator of CYP7A1. However, CYP7A1 expression is increased in FTF+/- liver. Gene expression profiles indicate that higher CYP7A1 expression is caused by attenuated liver cell stress signaling. Diet experiments support a model where FTF is quenched both by activated c-Jun, and by SHP as a stronger feedback mechanism to repress CYP7A1. A DR4 element is conserved in the FTF gene promoter and activated by LXR-RXR and TR-RXR, qualifying the FTF gene as a direct metabolic sensor. Liver FTF increases in rats treated with thyroid hormone or a high cholesterol diet. The FTF DR4 element tightens functional links between FTF and LXRalpha in cholesterol homeostasis and can explain transient surges of FTF gene activities during development and FTF levels lower than predicted in FTF+/- liver. The FTF-lacZ mouse establishes a central role for FTF in developmental, nutritive, and metabolic functions from early embryogenesis through adulthood.
Paré
Jean-François
JF
Département de biologie médicale, Faculté de médecine, Le Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, Québec G1R 2J6, Canada.
Malenfant
Daniel
D
Courtemanche
Chantal
C
Jacob-Wagner
Mariève
M
Roy
Sylvie
S
Allard
Denis
D
Bélanger
Luc
L
D000375:Aging / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002784:Cholesterol / Q000378:metabolism; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D005314:Embryonic and Fetal Development / Q000235:genetics*; D005313:Fetal Death / Q000235:genetics; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D020043:Genes, Essential; D006706:Homeostasis; D008099:Liver / Q000196:embryology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D013234:Stem Cells / Q000502:physiology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*; D001616:beta-Galactosidase / Q000235:genetics
D017931:DNA Primers; D004268:DNA-Binding Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C105190:TNFRSF10A protein, human; D014157:Transcription Factors; C099948:fetoprotein transcription factor; D002784:Cholesterol; D001616:beta-Galactosidase