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Altered Hox expression and segmental identity in Mll-mutant mice
B D Yu1, J L Hess, S E Horning
1Howard Hughes Medical Institute, Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Nature
|November 30, 1995
Summary
The mixed-lineage leukaemia gene (MLL) is crucial for embryonic development and maintaining segment identity in mammals. MLL deficiency causes severe developmental defects and impacts Hox gene expression, highlighting its essential regulatory role.
Area of Science:
- Developmental Biology
- Genetics
- Cancer Biology
Background:
- The mixed-lineage leukaemia gene (MLL) is implicated in human acute leukaemias with mixed lymphoid-myeloid phenotypes.
- MLL shares a conserved SET domain with Drosophila trithorax (trx) and Polycomb group (Pc-G) genes, regulators of homeotic genes (HOM-C).
Purpose of the Study:
- To investigate the role of MLL in mammalian pattern development using a mouse model.
- To assess the consequences of MLL disruption on embryonic development and gene regulation.
Main Methods:
- Targeted disruption of the Mll gene in mouse embryonic stem (ES) cells via homologous recombination.
- Analysis of Mll heterozygous (+/-) and deficient (-/-) mice for developmental and haematopoietic abnormalities.
- Examination of Hox gene expression patterns (Hoxa-7, Hoxc-9) in Mll mutant embryos.
Main Results:
- Mll heterozygous mice exhibited growth retardation, haematopoietic abnormalities, and homeotic transformations of the axial skeleton.
- Mll deficiency resulted in embryonic lethality.
- Anterior boundaries of Hoxa-7 and Hoxc-9 expression were posteriorly shifted in Mll +/- embryos and abolished in Mll -/- embryos.
Conclusions:
- MLL is essential for proper segment identity in mammals.
- MLL displays haplo-insufficiency, with heterozygous mutations causing significant developmental defects.
- MLL positively regulates Hox gene expression, underscoring its critical role in developmental patterning.