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 -/-/Alx4 lstD/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 -/-/Alx4 lstD/lstD embryos were recovered beyond 9.5 dpc. Between E8.5 and E10, viable Lef1 -/-/Alx4 lstD/lstD embryos were developmentally delayed 0.5 days relative to littermates of all other genotypes. Principle among the alterations seen in Lef1 -/-/Alx4 lstD/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 -/-/Alx4 lstD/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.

A 20 bp Duplication in Exon 2 of the Aristaless-Like Homeobox 4 Gene (ALX4) Is the Candidate Causative Mutation for Tibial Hemimelia Syndrome in Galloway Cattle

“…g . SHH, lymphoid enhancer-binding factor 1 (LEF1), exostosin 2 (EXT2), sex determining region Y-box 10 (SOX10), ALX homeobox 1 (ALX1), and GLI family zinc finger 3 (GLI3) [3–7]. Expression of ALX4 has been detected in osteoblast precursors of most bones, the dermal papilla of hair and whisker follicles, the dental papilla of teeth, and a subset of mesenchymal cells in pubescent mammary glands [8].…”

Wnt Signaling in Mammary Glands: Plastic Cell Fates and Combinatorial Signaling

“…If dkk1 is overexpressed in the basal keratinocyte layer (using a CK14 promoter) or when Lef1 function is missing (Boras-Granic et al 2006b;BorasGranic and Wysolmerski 2008), mammary specification is inhibited. Wnt10b is expressed at the earliest time during differentiation of the mammary placode (Veltmaat et al 2004;Boras-Granic and Wysolmerski 2008), suggesting that Wnt10b could be the placode specifier.…”

Circular RNA Circ_0000098 Elevates ALX4 Expression via Adsorbing miR-1204 to Inhibit the Progression of Hepatocellular Carcinoma

“…ALX4 is a member of the PRD subfamily of the homeobox gene (30). ALX4 is widely expressed in various tissues and organs, and features prominently in embryonic development and epidermal growth (31,32). Previous studies authenticate that the hypermethylation of ALX4 gene is found in colorectal cancer and bladder cancer tissues, which can be used as a candidate biomarker (33,34); ALX4 expression is decreased in breast cancer tissues and cells, and it inhibits the progression of breast cancer by interfering with Wnt/b-catenin pathway (35); in ovarian cancer, ALX4 promotes invasion and EMT of ovarian cancer cells by raising SLUG expression (36); ALX4 expression is declined in HCC tissues, and ALX4 overexpression impedes the multiplication, invasion, and EMT process of HCC cells (37).…”