title: Mice carrying a hypomorphic Evi1 allele are embryonic viable but exhibit severe congenital heart defects.
abstract: The ecotropic viral integration site 1 (Evi1) oncogenic transcription factor is one of a number of alternative transcripts encoded by the Mds1 and Evi1 complex locus (Mecom). Overexpression of Evi1 has been observed in a number of myeloid disorders and is associated with poor patient survival. It is also amplified and/or overexpressed in many epithelial cancers including nasopharyngeal carcinoma, ovarian carcinoma, ependymomas, and lung and colorectal cancers. Two murine knockout models have also demonstrated Evi1's critical role in the maintenance of hematopoietic stem cell renewal with its absence resulting in the death of mutant embryos due to hematopoietic failure. Here we characterize a novel mouse model (designated Evi1(fl3)) in which Evi1 exon 3, which carries the ATG start, is flanked by loxP sites. Unexpectedly, we found that germline deletion of exon3 produces a hypomorphic allele due to the use of an alternative ATG start site located in exon 4, resulting in a minor Evi1 N-terminal truncation and a block in expression of the Mds1-Evi1 fusion transcript. Evi1(δex3/δex3) mutant embryos showed only a mild non-lethal hematopoietic phenotype and bone marrow failure was only observed in adult Vav-iCre/+, Evi1(fl3/fl3) mice in which exon 3 was specifically deleted in the hematopoietic system. Evi1(δex3/δex3) knockout pups are born in normal numbers but die during the perinatal period from congenital heart defects. Database searches identified 143 genes with similar mutant heart phenotypes as those observed in Evi1(δex3/δex3) mutant pups. Interestingly, 42 of these congenital heart defect genes contain known Evi1-binding sites, and expression of 18 of these genes are also effected by Evi1 siRNA knockdown. These results show a potential functional involvement of Evi1 target genes in heart development and indicate that Evi1 is part of a transcriptional program that regulates cardiac development in addition to the development of blood.
authors.affiliation: Institute of Molecular and Cell Biology, Singapore, Singapore.
authors.forename: Emilie A
authors.initials: EA
authors.lastname: Bard-Chapeau
authors.affiliation: Welcome Trust Centre for Human Genetics, Oxford, United Kingdom.
authors.forename: Dorota
authors.initials: D
authors.lastname: Szumska
authors.affiliation: Cancer Science Institute, Singapore, Singapore.
authors.forename: Bindya
authors.initials: B
authors.lastname: Jacob
authors.affiliation: Institute of Molecular and Cell Biology, Singapore, Singapore.
authors.forename: Belinda Q L
authors.initials: BQ
authors.lastname: Chua
authors.affiliation: MYSM School of Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Gouri C
authors.initials: GC
authors.lastname: Chatterjee
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Molecular and Cell Biology, Singapore, Singapore.
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Ward
authors.affiliation: RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama, Japan.
authors.forename: Fatma
authors.initials: F
authors.lastname: Urun
authors.affiliation: RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Kinameri
authors.affiliation: Department of Development and Stem Cells, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, Inserm U964, Université de Strasbourg, Illkirch, France.
authors.forename: Stéphane D
authors.initials: SD
authors.lastname: Vincent
authors.affiliation: Institute of Molecular and Cell Biology, Singapore, Singapore.
authors.forename: Sayadi
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: Welcome Trust Centre for Human Genetics, Oxford, United Kingdom.
authors.forename: Shoumo
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Cancer Science Institute, Singapore, Singapore.
authors.forename: Motomi
authors.initials: M
authors.lastname: Osato
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Archibald S
authors.initials: AS
authors.lastname: Perkins
authors.affiliation: RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama, Japan.
authors.forename: Adrian W
authors.initials: AW
authors.lastname: Moore
authors.affiliation: Institute of Molecular and Cell Biology, Singapore, Singapore.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.affiliation: Institute of Molecular and Cell Biology, Singapore, Singapore.
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
mesh_terms: D000483:Alleles; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D001853:Bone Marrow / Q000473:pathology; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D004195:Disease Models, Animal; D005091:Exons; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal; D056726:Genetic Association Studies; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D016130:Immunophenotyping; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D011519:Proto-Oncogenes / Q000235:genetics*; D016415:Sequence Alignment; D012720:Severity of Illness Index; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C499305:Mecom protein, mouse; D014157:Transcription Factors