Overview
Our research group develops mouse models of human genetic disorders. Our primary focus area is mouse models of human disorders, with emphasis on Down syndrome and genetic conditions caused by spontaneous mutations in single genes. The Down syndrome mouse model we developed, Ts65Dn is currently considered to be the best animal model for studying this disease. It has three copies of about 60 percent of the related human chromosome 21 genes, survives into adulthood and exhibits many of the behavioral, learning, muscular and neuronal defects associated with the syndrome in humans. We study the basic biology of these mice and collaborate with external colleagues to identify genes involved in the neurobiology of Down syndrome, central nervous system signaling pathways, behavior and cognition, vision, hearing and reproduction. For single gene mutations, we carry out genetic analysis, frequently to the point of identifying the mutated gene, and sufficient phenotype characterization to make the model valuable for other scientists' research.
Scientific report
Ts65Dn, A Mouse Model for Down Syndrome
Down syndrome (DS) is the most common genetically defined cause of human mental retardation. DS is a complex, contiguous gene syndrome caused by triplication (trisomy) of all or most of the genes on chromosome 21. We have created a mouse model, Ts65Dn, that is the most complete model for DS and have used this model to study the basic biology of DS. Human chromosome 21 is conserved in mouse Chromosomes 10 (~2.3 Mb), 16 (~26.5 Mb) and 17 (~1.1 Mb). Our Ts(1716)65Dn segmental trisomy mouse model (designated Ts65Dn) carries, in a small extra chromosome, three copies of >75 percent of the Chromosome 16 orthologous genes - extending from Mrp139 (mitochondrial ribosomal protein L39) through the telomere (~14 Mb and ~124 genes). The Ts65Dn chromosome also contains the centromere with the adjacent proximal segment (~2 Mb) of Chromosome 17. The pattern and incidence of pathologic lesions observed in adult Ts65Dn mice does not differ from that of normal littermate controls. Males are functionally sterile. Analysis of meiosis and fertility, in collaboration with Dr. Mary Ann Handel, The Jackson Laboratory, showed Ts65Dn males have substantially reduced sperm numbers and a high proportion of the sperm present are abnormal. Comparison of fertility and meiosis in males of Ts65Dn (and three other segmental trisomies carrying an extra small chromosome) with males carrying a trisomic segment comparable to the Ts65Dn segment but attached to another chromosome (Ts1Cje) suggests that the presence of the extra Ts65Dn chromosome is the basis for sperm abnormality and sterility. In collaboration with others, we have studied central nervous system signaling pathways (Dr. Katheleen Gardiner at The Eleanor Roosevelt Institute, University of Denver, Denver, Colo., and Dr. Gilbert Di Paolo at Columbia University, New York, N.Y.), behavior and cognition (Dr. Alberto C.S. Costa at the University of Colorado Health Science Center), vision (Dr. Bo Chang at The Jackson Laboratory, Dr. Steve Nussinowitz at UCLA, and Dr. Alberto C.S. Costa at the University of Colorado Health Science Center), hearing (Drs. Qing Yin Zheng and Jiangping Zhang at Case Western Reserve University, Cleveland, Ohio, formerly at The Jackson Laboratory), reproduction (Drs. Mary Ann Handel and Laura Reinholdt, at The Jackson Laboratory), and stem cell biology (Dr. David Harrison, The Jackson Laboratory, and Dr. Paul Yarowsky at the University of Maryland, Baltimore, Md.).
Lab staff
Principal Investigator: Muriel T. Davisson, Ph.D.Adjunct Professor: Roderick T. Bronson, D.V.M.
Executive Assistant: Aimée Picard
Publication listings
Selected Publications
Donahue LR, Hrabe de Angelis M, Hagn M, Franklin C, Lloyd KCK, Magnuson T, McKerlie C, Nakagata N, Obata Y, Read S, Wurst W, Horlein A, Davisson MT. 2012. Centralized Mouse Repositories, Mammalian Genome 2012 Sep 4 (Epub ahead of print). PMID:22945696.
Davisson MT, Bergstrom DE, Reinholdt LG, Donahue LR. Discovery Genetics: The History and Future of Spontaneous Mutation Research, Curr Protocol Mouse Biol. 2012; 2:103-118.
Ahmed MM, Sturgeon X, Ellison M, Davisson MT, Gardiner KJ. 2012. Loss of correlations among proteins in brains of the Ts65Dn mouse model of Down syndrome. J Proteome Res. 2012 Jan 3. [Epub ahead of print]. PMID: 22214338.
Davisson MT, Bronson RT, Tadenev ALD, Motley WM, Krishnaswamy A, Seburn KL, Burgess RW. 2012. A Spontaneous Mutation in Contactin 1 in the Mouse. PLoS ONE 6: e29538. Lindfors C, Nilsson IA, Garcia-Roves PM, Zuberi AR, Karimi M, Donahue LR, Roopenian DC, Mulder J, Uhlén M, Ekström TJ, Davisson MT, Hökfelt TG, Schalling M, Johansen JE. Hypothalamic mitochondrial dysfunction associated with anorexia in the anx/anx mouse. Proc Natl Acad Sci U S A. 2011 Oct 24. [Epub ahead of print] PMID: 22025706 Reinholdt LG, Ding Y, Gilbert GT, Czechanski A, Solzak JP, Roper RJ, Johnson MT, Donahue LR, Lutz C, Davisson MT. Molecular characterization of the translocation breakpoints in the Down syndrome mouse model Ts65Dn. Mamm Genome. 2011 Sep 28. [Epub ahead of print] PubMed PMID: 21953412.Howng SY, Avila RL, Emery B, Traka M, Lin W, Watkins T, Cook S, Bronson R, Davisson M, Barres BA, Popko B. 2010. ZFP191 is required by oligodendrocyte for CNS myelination. [Epub 2010 Jan 15]. Genes Dev 24(3):301-11.
Scott-McKean JJ, Chang B, Hurd RE, Nusinowitz S, Schmidt C, Davisson MT, Costa AC. 2010. The Mouse Model of Down Syndrome Ts65Dn Presents Visual Deficits as Assessed by Pattern Visual Evoked Potentials. Invest Opthalmol Vis Sci [Epub ahead of print 2010 Feb 3].
Cook SA, Collin GB, Bronson RT, Naggert JK, Liu DP, Akeson EC, Davisson MT. 2009. A mouse model for Meckel syndrome type 3. J Amer Soc Nephrol 20:753-64.
Costa AC, Stasko MR, Schmidt C, Davssion MT. 2009. Behavioral validation of the Ts65Dn mouse model for Down syndrome of a genetic background free of the retinal degeneration mutation Pdeb (rd1), doi:10.1016/j.bbr.2009.08.034. [Epub ahead of print]. Behav Brain Res 206(2010):52-62.
Han F, Yua H, Zhanga J, Tiana C, Schmidt C, Navaa C, Davisson MT, Zheng QY. 2009. Otitis media in a mouse model for Down syndrome. http://www3.interscience.wiley.com/journal/122603153/abstract. Int J Exp Pathol 90(5):480-8.
Chang B, Mandal MNA, Chavali VRM, Hawes NL, Khan NW, Hurd RE, Smith RS, Davisson MT, Kopplin L, Klein BEK, Klein R, Lyengar SK, Heckenlively JR. Ayyagari R. 2008. Age-related retinal degeneration (aard20 in a novel mouse model due to a nonsense mutation in the Mdm1 gene. http://hmg.oxfordjournals.org/cgi/content/abstract/17/24/3929. Hum Mol Genet 17(24):3929-41.
Jin N, Chow CY, Liu L, Zolov SN, Bronson R, Davisson M, Peterson JL, Zhang Y, Park S, Duex JE, Goldowitz D, Meisler Mh, Weisman LS. 2008. VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse. EMBO J 27(24):3221-34.
Voronov SV, Frere SG, Giovedi S, Pollina EA, Borel C, Zhang H, Schmidt C, Akeson EC, Wenk MR, Cimasoni L, Arancio O, Davisson MT, Antonarakis SE, Gardiner K, De Camilli P, Di Paolo G. 2008. Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down's syndrome. Proc Natl Acad U S A 105(27):9415-20.
Chang B, Hawes NL, Pardue MT, German AM, Hurd RE, Davisson MT, Nusinowitz S, Regnarajan K, Boyd AP, Sidney SS, Phillips MJ, Stewart RE, Chaudhury R, Nickerson JM, Heckenlively JR, Boatright JH. 2007. Two mouse retinal degenerations caused by missense in the beta-subunit of rod cGMP phosphodiesteraase gene. Vis Res 47:624-633.
Davisson M, Akeson E, Schmidt C, Harris B, Farley J, Handel MA. 2007. Impact of trisomy on fertility and meiosis in male mice. Hum Reprod 22:468-476.
Du Y, Stasko M, Costa AC, Davisson MT, Gardiner KJ. 2007. Editing of the serotonin 2C receptor pre-mRNA: effects of the Morris Water Maze. Gene 391:186-197.
Simon-Chazottes D, Tutois S, Kuehn M, Evans M, Bourgade F, Cook S, Davisson MT, Guenet J-L. 2006. Mutations in the gene encoding the low-density lipoprotein receptor LRP4 cause abnormal limb development in the mouse. Genomics 87:673-677.
Taft RA, Davisson MT, Wiles MV. 2006. Know thy mouse. Trends Genet 22(12):649-653.
Lee JW, Beebe K, Nangle LA, Jang J, Longo-Guess C, Cook SA, Dvisson MT, Sundberg JP, Schimmel P, Ackerman SL. 2006. Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration in the sticky mouse. Nature 443:50-55.
Gilbert SL, Zhang L, Forster ML, Iwase T, Soliven B, Donahue LR, Sweet HO, Bronson RT, Davisson MT, Wollmann RL, Lahn BT. 2006. Trak1 mutation disrupts GABA(A) receptor homeostasis in hypertonic mice. Nat Genet 38(2):245-50.
FIMRe Board of Directors [Muriel Davisson, corresponding author]. 2006. FIMRe: Federation of International Mouse Resources: Global Networking of Resource Centers. Mamm Genome 17(5):363-364.
Du Y, Stasko M, Costa AC, Davisson MT, Gardiner KJ. 2006. Editing of the serotonin 2C receptor pre-mRNA: effects of the Morris Water Maze, GENE, ER. Genet Behav 36:439-453.
Du Y, Davisson MT, Kafadar K, Gardiner K. 2006. A-to-I pre-mRNA editing of the serotonin 2C receptor: comparisons among inbred mouse strains. Gene 382:39-46.
Davisson MT, Taft RA. 2006. Strategies for managing an ever increasing mutant mouse repository. Brain Res 1091:255-257.
Davisson M, Rockwood S. 2006. The benefits of strain donation. Immunity 24(1):3.
Book Chapters
Davisson MT, Linder CC. 2004. Historical Functions. In: The Laboratory Mouse, The Handbook of Experimental Animals, Hedrich, HJ, Bullock G, Petrusz P, [eds], Elsevier Academic Press, San Diego, CA, pp. 15-24.
Linder CC, Davisson MT. 2004. Strains, Stocks, and Mutant Mice. In: The Laboratory Mouse, The Handbook of Experimental Animals, Hedrich, HJ, Bullock G, Petrusz P. [eds], Elsevier Academic Press, San Diego, CA, pp. 25-46.
Davisson MT. 2006. Genetic Mapping. In: Mouse in Biomedical Research, 2nd edition, Volume 1 Fox J, Barthold S, Davisson MT, Newcomer C, Quimby F, Smith A (eds.), Elsevier, Inc., San Diego, CA, Chapter 7 pp. 115-133.
Davisson MT, Handel MA. 2006. Cytogenetics. In: Mouse in Biomedical Research, 2nd edition, Volume 1, Fox J, Barthold S. Davisson MT, Newcomer C, Quimby F, Smith A (eds.), Elsevier, Inc., San Diego, CA, Chapter 9 pp. 145-164.
Chang B, Hawes NL, Davisson MT, Heckenlively JR. 2007. Mouse Models of RP. In: Retinal Degnerations: Biology, Diagnostics, and Therapeutics. Tombran-Tink J, Barnstable CJ (eds.), The Humana Press, Inc., Totowa, NJ, pp. 149-164.