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 lar ge multidomain protein and bears homology to the Drosophila developmental c ontrol gene trithorax in two small domains in the amino terminal region, th e central zinc finger domain and the carboxy SET domain. Like the Drosophil a trx, MLL has also been shown to be a positive regulator of Hox gene expre ssion. We have targeted MII (the murine homologue of MLL) in exon 5 causing expression of three truncated in-frame MII transcripts. These transcripts retain all or some of the AT hook motifs and the DMT domain. This mutant al lele causes early in vivo preimplantation lethality of homozygous embryos p rior 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. (C ) 2001 Wiley-Liss, Inc.