Altered Hox expression and segmental identity in Mll-mutant mice.
The mixed-lineage leukaemia gene (MLL/HRX/ALL-1) is disrupted by chromosomal translocation in human acute leukaemias that often display mixed lymphoid-myeloid phenotypes and present in infancy. MLL possesses a highly conserved SET domain also found in Drosophila trithorax (trx) and Polycomb group (Pc-G) genes, which are known to regulate homeotic genes (HOM-C) in a positive or negative fashion, respectively. Mll was targeted in mice by homologous recombination in embryonic stem (ES) cells to assess its role in pattern development. Mll heterozygous (+/-) mice had retarded growth, displayed haematopoietic abnormalities, and demonstrated bidirectional homeotic transformations of the axial skeleton as well as sternal malformations. Mll deficiency (-/-) was embryonic lethal. Anterior boundaries of Hoxa-7 and Hoxc-9 expression were shifted posteriorly in Mll +/- embryos, but their expression was abolished in Mll -/- embryos. Thus Mll is required for proper segment identity in mammals, displays haplo-insufficiency, and positively regulates Hox gene expression.
D000818:Animals; D002460:Cell Line; D002678:Chimera; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005314:Embryonic and Fetal Development / Q000235:genetics / Q000502:physiology*; D005260:Female; D005333:Fetus / Q000002:abnormalities; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D005801:Genes, Homeobox; D006579:Heterozygote; D011495:Histone-Lysine N-Methyltransferase; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D016296:Mutagenesis; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein; D011519:Proto-Oncogenes; D014157:Transcription Factors
D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse