title: Genetic interaction between Lef1 and Alx4 is required for early embryonic development.
abstract: Lymphoid Enhancer Factor-1 (Lef1) facilitates the assembly of transcriptional regulatory complexes and mediates nuclear responses to Wnt signals. We determined previously that the mesenchymally restricted, paired-like homeodomain protein Aristaless-like 4 (Alx4) interacts with Lef1 and together alters promoter activity of candidate genes. In order to define their overlapping functions, mice deficient for both Lef1 and Alx4 activity (Lef1-/-/Alx4lstD/lstD) were produced. Whereas embryos lacking either Lef1 or Alx4 activity remain viable up to or after birth, early embryonic lethality results when both factors were absent. No viable Lef1-/-/Alx4lstD/lstD embryos were recovered beyond 9.5 dpc. Between E8.5 and E10, viable Lef1-/-/Alx4lstD/lstD embryos were developmentally delayed 0.5 days relative to littermates of all other genotypes. Principle among the alterations seen in Lef1-/-/Alx4lstD/lstD animals was defective vasculature in both embryonic and extra-embryonic tissues. In the yolk sac, while the vascular network is present, it were greatly diminished and large vitelline vessels were largely absent. Platelet/endothelial cell adhesion molecule (PECAM) staining revealed that the major vessels in the head of compound mutant embryos were absent, while the other vessels were finer than those seen in normal littermates. Pools of blood and pericardial effusion were also apparent in Lef1-/-/Alx4lstD/lstD animals, further indicative of a defective vasculature. These data confirm genetically the interaction between Lef1 and Alx4 and further reveal unknown, overlapping roles for these transcription factors in embryonic vasculogenesis.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
authors.forename: Kata
authors.initials: K
authors.lastname: Boras-Granic
authors.forename: Rudolf
authors.initials: R
authors.lastname: Grosschedl
authors.forename: Paul A
authors.initials: PA
authors.lastname: Hamel
mesh_terms: D000818:Animals; D003433:Crosses, Genetic; D047108:Embryonic Development; D005260:Female; D019085:Fluorescent Antibody Technique, Direct; D018507:Gene Expression Regulation, Developmental; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000196:embryology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011247:Pregnancy; D015017:Yolk Sac / Q000098:blood supply
chemical_list: C109218:Alx4 protein, mouse; D018398:Homeodomain Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D019408:Platelet Endothelial Cell Adhesion Molecule-1