|Department Affiliations||Department of Physiology, McKusick-Nathans Institute for Genetic Medicine|
|SOM Address||Room 201 Biophysics Building|
Trisomy 21 causes Down syndrome (DS), the most complex genetic insult compatible with human survival. Every cell in the body is affected by increased expression of Chr21 genes leading many to conclude that amelioration will not be successful; we have recently demonstrated that this is incorrect. Using mouse models with dosage imbalance for the same genes triplicated in Down syndrome, we characterized a new neurobiological phenotype in Ts65Dn mice a cerebellar granule cell deficit and showed that it occurs in humans with DS. Quantitative morphological assessments across cerebellar development determined the time when the trisomic cerebellum diverges from euploid, identified the affected cells and characterized the deficit as a reduced level of mitosis in trisomic cells. Compound transgenic mice and growth factor treatment of primary cultures of developing neurons demonstrated that reduced mitosis was due to impaired response to Shh growth factor in vivo and in vitro. These findings allowed us to initiate a specific therapy to ameliorate this neurobiological anomaly using a small molecule agonist of the Shh pathway. Our comprehensive approach to genotype-phenotype assessment includes genomics and comparative sequencing, array analysis and proteomics, behavioral genetics, neurobiology, transgenic/ES cell approaches and morphometric analyses across development.
For nearly 50 years, conflicting epidemiological data has been accumulated regarding the issue of whether solid tumor incidence is reduced in Down syndrome. Three very large studies of death records suggest that this tumor suppression does occur, but disagree as to which tumor types are inhibited by trisomy. We have established direct experimental evidence showing that trisomy does infer protection from tumors and that a protective effect can be seen in mice trisomic for a small subset of chromosome 21 orthologs. Experiments are underway to identify the dosage sensitive tumor suppressor gene(s) that are responsible.
Analysis of non-small cell lung carcinomas led to the positional cloning and characterization of a tumor suppressor gene, TSLC1, that is capable by itself of reversing the transformed phenotype of lines derived from a number of solid tumors. Further work identified carbonyl-reductase 1 as a target for amelioration of cardiotoxicity after administration of the otherwise highly effective cancer drug, doxorubicin.
- Reeves, RH, LL Baxter and JT Richtsmeier. 2001. Too much of a good thing: Mechanisms of gene action in Down syndrome. Trends in Genetics 17:83-88.
- 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.
- 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.
- Olson, L.E., D. Bedja, S.J. Alvey, A.J. Cardounel, K.L. Gabrielson and R.H. Reeves. Protection from doxorubicin-induced cardiac toxicity in Mice with a null allele of Carbonyl Reductase 1 (Cbr1). Cancer Research 63: 6602-6606.
- Olson, L.E., Richtsmeier, J.T., Leszl, J. and Reeves, R.H. 2004. Direct testing refutes a Chromosome 21 Critical Region as the cause of Down syndrome phenotypes. Science 306:687-690.