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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.

Pubmed ID: 7477409

Authors

  • Yu BD
  • Hess JL
  • Horning SE
  • Brown GA
  • Korsmeyer SJ

Journal

Nature

Publication Data

November 30, 1995

Associated Grants

None

Mesh Terms

  • Animals
  • Cell Line
  • Chimera
  • DNA-Binding Proteins
  • Embryonic and Fetal Development
  • Female
  • Fetus
  • Gene Expression Regulation, Developmental
  • Gene Targeting
  • Genes, Homeobox
  • Heterozygote
  • Histone-Lysine N-Methyltransferase
  • Homozygote
  • Humans
  • Male
  • Mice
  • Mutagenesis
  • Mutation
  • Myeloid-Lymphoid Leukemia Protein
  • Proto-Oncogenes
  • Transcription Factors