Assistant Professor of Oncology
Department of Cancer Genetics

Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo, NY 14263
Telephone: (716)845-1099
Fax: (716)845-1698
E-mail: Yuejin.Yu@RoswellPark.org

General Research Interest

Mouse models of childhood cancer and other human diseases

Current Program

Modeling human trisomy 21 using mouse chromosome engineering technology

Laboratory Personnel

Annie Pao BS
Chunhong Liu, PhD
Tao Yu, PhD

Description of Research

Trisomy 21 is the most frequent live-born human aneuploidy. It causes a constellation of clinical features classified as Down syndrome, which includes mental retardation, childhood leukemia, and early-onset Alzheimer-like neurodegeneration. Because of the existence of highly conserved homologous regions between human chromosome 21 and three segments of the mouse genome on chromosomes 10, 16, and 17, mice are suitable for modeling human trisomy 21. Three strains trisomic for regions of mouse chromosome 16 have been derived from balanced chromosomal translocations. In the genomes of these animals, about 120 mouse orthologs of human chromosome 21 genes have three copies. These models have been instrumental for elucidating the trisomic effects of specific genomic regions on the phenotypes. However, several major clinical features of Down syndrome, including leukemia, have not been conclusively established in these models. This discrepancy is likely caused by the other approximately 100 genes on human chromosome 21 that are not trisomic in the current models.

To dissect the molecular mechanisms of Down syndrome, it is desirable to generate animal models that truly mimic this genomic defect at both the genotypic and phenotypic levels. To achieve that goal, we have started generating a new mouse model trisomic for all the chromosomal segments that are homologous to the regions on human chromosome 21. The genomic duplications are being generated using chromosome engineering technology. The availability of the human chromosome 21 sequence and the mouse genome sequence has greatly facilitated the selection of the end points for engineering the duplications. The selected end points are located immediately outside the mouse chromosomal segments that are conserved on human chromosome 21. To generate a duplication, two loxP sites are targeted into the two end points of the rearrangement in the mouse embryonic stem (ES)-cell genome. These ES cells are then transfected with a Cre-expression vector to induce recombination between the two targeted loxP sites, thereby generating the desired duplication. The engineered ES cells will be used to establish three mouse lines, and each line will carry a duplication of one of the conserved segments. Afterwards, the different lines will be crossed to establish triple heterozygous duplications, and thus a new mouse model of Down syndrome. The mouse lines carrying heterozygous duplications will be systematically characterized to identify the phenotypic features of Down syndrome. These mutant mice can provide tissues that are required to examine the developmental consequences of human trisomy 21. They can also be used for the development of novel therapeutic interventions for Down syndrome patients. In the future, we will engineer smaller overlapping duplications within the mouse chromosomal regions homologous to the trisomic human chromosome 21 regions to identify the crucial genomic domain(s) and causative gene(s).

Children with Down syndrome have a 10-20-fold increased risk of developing leukemia. As many as 10% of infants with Down syndrome develop transient leukemia and approximately 30% of these patients develop acute megakaryoblastic leukemia. Recent evidence showed that acquired mutations of GATA1 were a key event in the development of transient leukemia in Down syndrome patients (Wechsler et al., Nature Genetics, 2002, 32: 148-152; Groet et al., Lancet, 2003, 361: 1617-1620). We will generate a desired Gata1 mutation in mice using gene targeting and ES cell technology and then transfer this mutation to the genome of the aforementioned mouse model of Down syndrome. The resultant mutant mice will be used to analyze molecular events associated with leukemia in Down syndrome patients.

Chromosomal deletions and translocations are also critical genetic alterations in the formation of many types of human tumors. We are also interested in modeling these tumor-associated genomic rearrangements using mouse chromosome engineering technology.

Key Publications

• Li Z, Yu T, Morishima M, Pao A, Laduca J, Conroy J, Nowak N, Matsui SI, Shiraishi I, Yu YE. Duplication of the entire 22.9 Mb human chromosome 21 syntenic region on mouse chromosome 16 causes cardiovascular and gastrointestinal abnormalities. Hum Mol Genet 2007;16(11):1359-1366.
• Yu YE, Morishima M, Pao A, Wang DY, Wen XY, Baldini A, Bradley A.  A deficiency in the region homologous to human 17q21.33-q23.2 causes heart defects in mice.  Genetics 2006; 173:297-307.
• Hentges KE, Nakamura H, Furuta Y, Yu, Y, Thompson DM, O'Brien W, Bradley A, Justice MJ.  Novel lethal mouse mutants produced in balancer chromosome screens.  Gene Exp Patterns 2006; 6:653-665.
• Li Z, Szurek PF, Jiang C, Pao A, Bundy BN, Le W-D, Bradley A, Yu YE. Neuronal differentiation of NTE-deficient embryonic stem cells. Biochem Biophys Res Comm 2005; 330:1103-1109.
• Adams DJ, Biggs PJ, Cox T, Davies R, van der Weyden L, Jonkers J, Smith J, Plumb B, Taylor R, Nishijima I, Yu Y, Rogers J, Bradley A.  Mutagenic insertion and chromosome engineering resource (MICER). Nat Genet 2004; 36:867-871.
• Chung Y-J, Jonkers J, Kitson H, Fiegler H, Humphray S, Scott C, Hunt S, Yu, Y, Nishijima I, Velds A, Holstege H, Carter N, Bradley A. A whole-genome mouse BAC microarray with 1 Mb resolution for analysis of DNA copy number changes by array comparative genomic hybridization. Genome Res 2004; 14:188-196.
• Yu Y, and Bradley A. Engineering chromosomal rearrangements in mice. Nat Rev Genet 2001; 2:780-790.
• Zhao M, Shirley CR, Yu YE, Mohapatra B, Zhang Y, Unni E, Deng GM, Arango NA, Weil M, Russell LD, Behringer RR, Meistrich ML. Targeted disruption of the transition protein 2 gene affects sperm chromatin structure and reduces fertility in mice. Molec Cell Biol 2001; 21:7243-7255.
• Yu YE, Unni E, Zhang Y, Christian C, Deng GM, Russell LD, Weil M, Behringer RR, Meistrich ML. Abnormal spermatogenesis and reduced fertility in transition nuclear protein 1?deficient mice. Proc Natl Acad Sci 2000; 97:4683-4688.
• Yu YE, Choe W, Zhang W, Stoica G, Wong PKY. Development of pathological lesions in the central nervous system of transgenic mice expressing the env gene of ts1 Moloney murine leukemia virus in the absence of the viral gag and pol genes and viral replication. J Neurovirology 1997; 3:274-282.
• Yu YE, Stoica G, Multani AS, Zhang W, Pathak S, Wong PKY. Characterization of a transgene-induced mutant mouse line which showed thymus atrophy and neuronal degeneration. Mouse Genome 1997; 95:704-706.