The Evil proto-oncogene is required at midgestation for neural, heart, and paraxial mesenchyme development

Abstract

The ecotropic viral integration site-1 (Evi1) locus was initially identified as a common site of retroviral integration in myeloid tumors of the AKXD-23 recombinant inbred mouse strain. The full-length Evi1 transcript encodes a putative transcription factor, containing ten zinc finger motifs found within two domains of the protein. To determine the biological function of the Evi1 proto-oncogene, the full-length, but not an alternately spliced, transcript was disrupted using targeted mutagenesis in embryonic stem cells. Evi1 homozygous mutant embryos die at approximately 10.5 days post coitum. Mutants were distinguished at 10.5 days post coitum by widespread hypocellularity, hemorrhaging, and disruption in the development of paraxial mesenchyme. In addition, defects in the heart, somites, and cranial ganglia were detected and the peripheral nervous system failed to develop. These results correlated with whole-mount in situ hybridization analyses of embryos which showed expression of the Evi1 proto-oncogene in embryonic mesoderm and neural crest-derived cells associated with the peripheral nervous system. These data suggest that Evi1 has important roles in general cell proliferation, vascularization, and cell-specific developmental signaling, at midgestation.

Significant increase of self-renewal in hematopoietic cells after forced expression of EVI1

“…These data also suggest that the mechanisms/pathways utilized by EVI1 are not independent of genetically encoded cellular characteristics. These data are in agreement with those of investigators who suggested that EVI1 might have a crucial function in cellular proliferation and differentiation [1] and that might promote the cell proliferation [14].…”

“…This paper is based on a presentation at the Seventh International Workshop on Molecular Aspects of Myeloid Stem Cell Development and Leukemia in Annapolis, Maryland, May [13][14][15][16] 2007, sponsored by The Leukemia & Lymphoma Society.…”

The EVI1 gene in myeloid leukemia

“…This is confirmed by recent work showing that the disruption of the full-length Evi1 transcript by targeted mutagenesis of embryonic stem cells results in the death of mutant embryos at approximately 10 5 . 26 Homozygous Evi1-/-embryos were readily identified by hemorrhaging and malformation of the paraxial mesoderm. Histological analysis revealed widespread hypocellularity, defective myotome formation, defects in the neural ectoderm, and failure of the peripheral nervous system to develop.…”

“…The cellular proliferation defects noted in mutant embryos would support the involvement of Evi1 in dysregulated cell growth observed in retrovirus-induced leukemias. 26 Studies of the function of murine and human EVI1 in bone 2024 marrow cells and in cell lines have shown that the inappropriate expression of EVI1 prohibits terminal differentiation in granulocytes, erythroid cells, and bone marrow progenitor cells. 27,28 Some of these studies utilized the IL-3-dependent murine cell line 32Dc13.…”

“…The results showed that disruption of egl-43 or Evi1 affects development of the nervous system. 18,26 The identification of the cDNAs of MDS1, EVI1, and MDS1/EVI1 and the overall homology of MDS1/EVI1 to egl-43 raises the question of the nature and relationship of the three human genes. Figure 5 shows the position of the known critical exons participating in the splice junctions, and indicates how the various transcripts could be generated.…”