Mammalian mutagenesis using a highly mobile somatic Sleeping Beauty transposon system.
Transposons have provided important genetic tools for functional genomic screens in lower eukaryotes but have proven less useful in higher eukaryotes because of their low transposition frequency. Here we show that Sleeping Beauty (SB), a member of the Tc1/mariner class of transposons, can be mobilized in mouse somatic cells at frequencies high enough to induce embryonic death and cancer in wild-type mice. Tumours are aggressive, with some animals developing two or even three different types of cancer within a few months of birth. The tumours result from SB insertional mutagenesis of cancer genes, thus facilitating the identification of genes and pathways that induce disease. SB transposition can easily be controlled to mutagenize any target tissue and can therefore, in principle, be used to induce many of the cancers affecting humans, including those for which little is known about the aetiology. The uses of SB are also not restricted to the mouse and could potentially be used for forward genetic screens in any higher eukaryote in which transgenesis is possible.
Dupuy
Adam J
AJ
National Cancer Institute, Center for Cancer Research, Frederick, Maryland 21702, USA.
Akagi
Keiko
K
Largaespada
David A
DA
Copeland
Neal G
NG
Jenkins
Nancy A
NA
D000483:Alleles; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004251:DNA Transposable Elements / Q000235:genetics*; D020964:Embryo Loss / Q000235:genetics; D004622:Embryo, Mammalian / Q000378:metabolism; D008322:Mammals / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional / Q000235:genetics* / Q000379:methods*; D009369:Neoplasms / Q000235:genetics; D009857:Oncogenes / Q000235:genetics; D010641:Phenotype; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D019895:Transposases / Q000235:genetics / Q000378:metabolism
D004251:DNA Transposable Elements; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D019895:Transposases