Truncation of the Mll gene in exon 5 by gene targeting leads to early preimplantation lethality of homozygous embryos.
The mixed lineage leukemia gene (MLL) was originally identified through its involvement in reciprocal translocations in leukemias. MLL codes for a large multidomain protein and bears homology to the Drosophila developmental control gene trithorax in two small domains in the amino terminal region, the central zinc finger domain and the carboxy SET domain. Like the Drosophila trx, MLL has also been shown to be a positive regulator of Hox gene expression. We have targeted Mll (the murine homologue of MLL) in exon 5 causing expression of three truncated in-frame Mll transcripts. These transcripts retain all or some of the AT hook motifs and the DMT domain. This mutant allele causes early in vivo preimplantation lethality of homozygous embryos prior to the 2-cell stage. Embryos cultured in vitro progress to the 2-cell stage, but further development is arrested. The heterozygotes exhibit mild skeletal defects as well as defects in some neuroectodermal derivatives.
Ayton
P
P
Imperial Cancer Research Fund, Medical Oncology Department, St. Bartholomew's and Royal London Hospital School of Medicine, London, United Kingdom.
Sneddon
S F
SF
Palmer
D B
DB
Rosewell
I R
IR
Owen
M J
MJ
Young
B
B
Presley
R
R
Subramanian
V
V
D000818:Animals; D001755:Blastocyst; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004475:Ectoderm / Q000378:metabolism; D020964:Embryo Loss / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005314:Embryonic and Fetal Development / Q000235:genetics; D005091:Exons / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D020043:Genes, Essential / Q000235:genetics*; D005804:Genes, Lethal / Q000235:genetics; D006579:Heterozygote; D011495:Histone-Lysine N-Methyltransferase; D006720:Homozygote; D008297:Male; D051379:Mice; D009139:Musculoskeletal Abnormalities / Q000235:genetics / Q000473:pathology; D016254:Mutagenesis, Insertional / Q000235:genetics*; D051788:Myeloid-Lymphoid Leukemia Protein; D010641:Phenotype; D011519:Proto-Oncogenes; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion / Q000235:genetics; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse