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Down syndrome (DS) occurs as a result of Trisomy 21 and is among the most complicated genetic conditions compatible with human survival. The Reeves laboratory complements genetic analyses in human beings with the creation and characterization of mouse models to understand why and how gene dosage imbalance disrupts development in DS. The models then provide a basis to explore therapeutic approaches to amelioration of DS features. We use chromosome engineering in ES cells to create defined dosage imbalance in order to localize the genes contributing to these anomalies and to test directly hypotheses concerning Down syndrome “critical regions” on human chromosome 21. Quantitative phenotypic assays that we have developed give a precise and sensitive readout of the relative effects on phenotype when overlapping subsets of genes are at dosage imbalance. Developmental analyses of these traits are underway to identify the timing and location of divergence between trisomic and euploid fetuses. We have used mouse models to:
- Validate epidemiological findings suggesting a lower incidence of cancer in Down syndrome and to identify the candidate genes (Sussan et al., 2008; Yang and Reeves, 2011) I
- Identify direct parallels in the development of the craniofacial skeleton in Down syndrome and trisomic mice (see Hill et al., 2007; Starbuck et al., 2011) E
- Establish a deficit in cranial neural crest as the (initial) basis for the hypomorphic craniofacial skeleton skeleton (Roper et al., 2009)
- Discover the basis for and potential “treatment” of a fundamental structural deficit in the trisomic brain (Roper et al., 2006; Reeves and Garner, 2007; Currier et al., 2012)
Definition of the timing and location of divergence between trisomic and euploid phenotypes and of the gene(s) primarily contributing to those differences provides the necessary basis for genetic, pharmacologic and stem cell therapies to ameliorate these anomalies (Das and Reeves, 2011; Haydar and Reeves, 2012).
Genetic modifiers of Down syndrome features
Many features of Down syndrome have highly variable severity in different individuals with trisomy 21. In a multi-Institute collaboration we have combined genetic analysis of patient samples, candidate gene sequencing and mouse modeling to identify genetic modifiers producing congenital heart disease in human beings (DS Heart Project). The study is based on the 2000x elevation of complete AV canal or AVSD in Down syndrome. CHD is the most frequent birth defect in human beings regardless of ploidy. The increased “signal-to-noise” ratio for gene expression effects in Down syndrome will contribute to understanding and treatment of congenital heart disease in all people.
We have expanded this study to assess genetic contributions to variation in intellectual ability in the Down Syndrome Cognition Project (DS Cognition Project) [Please link to the new tab]. We use the Arizona Cognitive Test Battery (Edgin et al., 2010) to assess cognitive ability based on functions mapped to different brain regions that are often affected in Down syndrome. Johns Hopkins School of Medicine and the Kennedy Krieger Institute are a site for the ongoing Roche Clinical trial, BP 25543.
Additional information is available at Clinicaltrials.gov.
Haydar, T.F. and R.H. Reeves. 2012. Trisomy and early brain development. Trends in Neuroscience 35:81-91.
Li, H., S. Cherry, D. Klinedinst, V. DeLeon, J. Redig, B. Reshey, S.L. Sherman, C. Maslen and R.H. Reeves. 2012. Genetic modifiers predisposing to congenital heart disease in the sensitized Down syndrome population. Circ: Cardiovasc. Genet. 5(3):301-8.
Yang, A. and R.H. Reeves. 2011. Ts65Dn “Down syndrome” mice show increased survival in a complex cancer model. Cancer Res 71(10): 3573-81.
Starbuck, J.M., R.H. Reeves, J.T. Richtsmeier. 2011. Morphological Integration of Soft-Tissue Facial Morphology in Down Syndrome Individuals and Siblings. Am. J. Physical 146: 560-568.
Das, I. and R.H. Reeves. 2011. A crucial role for mouse models to understand and improve cognitive deficits in Down syndrome. Disease Models and Mechanisms 4:596-606.
Haydar, T.F. and R.H. Reeves. 2012. Trisomy and early brain development. Trends in Neuroscience 35:81-91. PubMed Reference Sussan T., A. Yang. F. Li, M. Ostrowski and R.H. Reeves. 2008. Trisomy protects against ApcMin-mediated tumors in mouse models of Down syndrome. Nature 451:73-5.
Roper, R.J.*, L.L. Baxter*, N. Saran, D. Klinedinst, P. Beachy and R.H. Reeves. 2006. Defective cerebellar response to mitogenic Hedgehog signaling in Down syndrome mice. Proc. Natl. Acad. Sci. 103(5):1452-6. *These authors contributed equally.
Roper, R.J., H.K. St. John, J. Philip, A. Lawler, R.H. Reeves. 2006. Perinatal loss of Ts65Dn mice, a model Down syndrome. Genetics 172(1):437-43.
Sussan, T., M. Pletcher, Y. Murakami, and R.H. Reeves. 2005. Tumor suppressor in lung cancer 1 (TSLC1) alters tumorigenic growth and gene expression in the non-small cell lung cancer cell line A549. Molecular Cancer 4:28.
Olson L.E., J.T. Richtsmeier, J. Leszl, and R.H. Reeves. 2004. Direct testing does not support a Chromosome 21 Critical Region as the cause of Down syndrome phenotypes when triplicated. Science 306:687-690.
Saran, N.G., M.T. Pletcher, J.E. Natale, Y. Ching and R.H. Reeves. 2003. Global Disruption of the Cerebellar Transcriptome in a Down Syndrome Mouse Model. Hum. Mol. Genet. 12:2013-9.
Kuramochi, M., H. Fukuhara, T. Nobukuni, T. Kanbe, T. Maruyama, H.P. Ghosh, M. Pletcher, M. Isomura, M. Onizuka, T. Kitamura, T. Sekiya, R.H. Reeves and Y. Murakami. 2001. TSLC1 is a tumor suppressor gene in human non-small cell lung cancer. Nature Genetics 27:427-430.
Richtsmeier, J.T., L.L. Baxter and R.H. Reeves. 2000. Parallels of craniofacial development in Down syndrome and Ts65Dn mice. Developmental Dynamics 217:137-145.
Reeves, R.H., N.G. Irving, T. Moran, A. Wohn, C. Kitt, S. Sisodia, C. Schmidt, R.T. Bronson and M.T. Davisson. 1995. A mouse model for Down Syndrome exhibits learning and behavior deficits. Nature Genetics 11:177-184.