Sally E. Spence

Hematopoietic, angiogenic and eye defects in Meis1 mutant animals

Meis1 and Hoxa9 expression is upregulated by retroviral integration in murine myeloid leukemias and in human leukemias carrying MLL translocations. Both genes also cooperate to induce leukemia in a mouse leukemia acceleration assay, which can be explained, in part, by their physical interaction with each other as well as the PBX family of homeodomain proteins. Here we show that Meis1‐deficient embryos have partially duplicated retinas and smaller lenses than normal. They also fail to produce megakaryocytes, display extensive hemorrhaging, and die by embryonic day 14.5. In addition, Meis1‐deficient embryos lack well‐formed capillaries, although larger blood vessels are normal. Definitive myeloerythroid lineages are present in the mutant embryos, but the total numbers of colony‐forming cells are dramatically reduced. Mutant fetal liver cells also fail to radioprotect lethally irradiated animals and they compete poorly in repopulation assays even though they can repopulate all hematopoietic lineages. These and other studies showing that Meis1 is expressed at high levels in hematopoietic stem cells (HSCs) suggest that Meis1 may also be required for the proliferation/self‐renewal of the HSC.

Genetic localization of Hao-1, blind-sterile (bs), and Emv-13 on mouse chromosome 2

The blind-sterile (bs) mutation in the mouse was localized on Chromosome 2 between Hao-1 and Emv-13. N2 progeny from a backcross between congenic female 129.AKR-bs Emv-13 mice and (129.AKR-bs/bs x Mus musculus molossinus) F1 male mice were typed by analysis of isozyme variants for Hao-1, visible inspection for bs, and restriction fragment length polymorphism for Emv-13 and Emv-15. Comparison between markers on mouse Chromosome 2 and corresponding markers on human chromosomes suggest that the human homolog of bs will be located on 20q11-q13.

Spontaneous Germ-Line Ecotropic Murine Leukemia Virus Infection: Implications for Retroviral Insertional Mutagenesis and Germ-Line Gene Transfer

Publisher Summary Ecotropic murine leukemia viruses (MuLWs) provide important tools for the study of mammalian development. Not only can they act as germ-line insertional mutagens, facilitating the identification and cloning of genes important in mammalian development, but they can also serve as vectors for the efficient delivery of genes into mammalian cells. This chapter presents implications for retroviral insertional mutagenesis and germ-line gene transfer. The development of inbred and/or hybrid strains of mice that spontaneously acquire new germ-line proviruses at high frequencies provide a technically simple experimental system for viral insertional mutagenesis and may ultimately allow for selected mutagenesis similar to what is now being done in Drosophila melanogaster with P elements. The development of such system has, however, been hindered by the low frequency at which ecotropic proviruses are spontaneously acquired in the mouse germ line. The identification of a hybrid mouse strain combination, SWR/J-RF/J, that has high frequencies of spontaneous provirus acquisition has enabled the execution of experiments designed to delineate the mechanism and developmental stage of provirus acquisition and to evaluate the potential of this approach for retroviral insertional mutagenesis. The results of these experiments have important implications for the use of retroviral vectors to introduce foreign genes into the germ line of mice and other mammalian species.