title: A novel mouse model for Down syndrome that harbor a single copy of human artificial chromosome (HAC) carrying a limited number of genes from human chromosome 21.
abstract: Down syndrome (DS), also known as Trisomy 21, is the most common chromosome aneuploidy in live-born children and displays a complicated symptom. To date, several kinds of mouse models have been generated to understand the molecular pathology of DS, yet the gene dosage effects and gene(s)-phenotype(s) correlation are not well understood. In this study, we established a novel method to generate a partial trisomy mice using the mouse ES cells that harbor a single copy of human artificial chromosome (HAC), into which a small human DNA segment containing human chromosome 21 genes cloned in a bacterial artificial chromosome (BAC) was recombined. The produced mice were found to maintain the HAC carrying human genes as a mini-chromosome, hence termed as a Trans-Mini-Chromosomal (TMC) mouse, and HAC was transmitted for more than twenty generations independent from endogenous mouse chromosomes. The three human transgenes including cystathionine β-synthase, U2 auxiliary factor and crystalline alpha A were expressed in several mouse tissues with various expression levels relative to mouse endogenous genes. The novel system is applicable to any of human and/or mouse BAC clones. Thus, the TMC mouse carrying a HAC with a limited number of genes would provide a novel tool for studying gene dosage effects involved in the DS molecular pathogenesis and the gene(s)-phenotype(s) correlation.
authors.affiliation: Laboratory of Gene Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Suzuki
authors.forename: Kosuke
authors.initials: K
authors.lastname: Sakai
authors.forename: Shuichi
authors.initials: S
authors.lastname: Asakawa
authors.forename: Tsuneko
authors.initials: T
authors.lastname: Okazaki
authors.forename: Jun
authors.initials: J
authors.lastname: Kudoh
authors.forename: Masashi
authors.initials: M
authors.lastname: Ikeno
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D022222:Chromosomes, Artificial, Human / Q000235:genetics*; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000378:metabolism; D018628:Gene Dosage / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes / Q000235:genetics