Overview
Our laboratory develops mouse models of human disorders. Our primary areas of focus are Down syndrome, the inherited human condition that results from an extra copy of Chromosome 2, and single gene mutations that cause kidney disease. We developed the trisomic mouse model (Ts65Dn) for Down syndrome, which is currently considered to be the best animal model for Down syndrome. 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. In our lab we study the basic biology of these mice and we 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.
Research details
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 Senior Staff Scientist: Roderick T. Bronson, D.V.M.
Executive Assistant: Debra R. Geaghan
Publication listings
Bauschatz JD, Curtain MM, Davisson MT, Lane PW, Donahue LR. 2003. In Collaboration: The Jackson Laboratory Craniofacial Resource, Special Issue: Honoring Dr. Sandy C. Marks, Jr., 1937-2002. Crit Rev Eukaryot Gene Expr 13(2-4):107-108.
Donahue LR, Chang B, Subburaman M, Miyakoshi N, Wergedal JE, Baylink DJ, Hawes NL, Rosen CJ, Ward-Bailey P, Zheng QY, Bronson RT, Johnson KR, Davisson MT. 2003. A missense mutation in the mouse Col2al gene causes spondyloepiphyseal dysplasia, hearing loss, and retinoschisis. J Bone Miner Res 18(9):1612-1621.
Gardiner K, Fortna A, Bechtel L, Davisson MT. 2003. Mouse models of Down syndrome: how useful can they be? Comparison of the gene content of human chromosome 21 with orthologous mouse genomic regions. Gene 318:137-147.
Johnson KR, Lane PW, Cook SA, Harris BS, Ward-Basiley PF, Bronson RT, Lyons BL, Shultz LD, Davisson MT. 2003. Curly bare (cub), a new mouse mutation on Chr 11 causing skin and hair abnormalities, and a modifier gene (Mcub) on Chr 5. Genomics 81(1):6-14.
Liu DP, Schmidt C, Billings T, Davisson MT. 2003. Quantitative PCR genotyping assay for the Ts65Dn mouse model of Down syndrome. BioTechniques 35:1170-1174.
Gardiner K, Davisson MT, Crnic LS. 2004. Building protein interaction maps for Down syndrome. Brief Funct Genomic Proteomic 3(2):142-156.
Lorenz-Depiereux B, Guido VE, Johnson KR, Zheng QY, Gagnon LH, Bauschatz JD, Davisson MT, Washburn LL, Donahue LR, Strom TM, Eicher EM. 2004. New intragenic deletions in the Phex gene clarify X-related hypophosphatemia-related abnormalities in mice. Mamm Genome 15(3):151-161.
Wenger GR, Schmidt C, Davisson MT. 2004. Operant conditioning in the Ts65Dn mouse: Learning. Behav Genet 34:105-19.
Zheng QY, Harris BS, Yu H, Letts VA, Ward-Bailey P, Bronson RT, Davisson MT, Johnson KR. 2004. Fine mapping of a deafness mutation hml on Mouse Chromosome 10. Academic Jounral of Xi'an Jiaotong University 25(2):105-109.
Chang B, Hawes NL, Hurd RE, Wang J, Howell D, Davisson MT, Roderick TH, Nusinowitz S, Heckenlively JR. 2005. Mouse models of ocular diseases. Vis Neurosci 22:587-593.
Davisson MT. 2005. Mouse models of Down syndrome. Drug Discovery Today: Disease Models 2:103-109.
Davisson MT. 2005. Discovery Genetics: Serendipity in Basic Research. ILAR J 46(4):338-345.
Gardiner K, Davisson MT, Pritchard M, Patterson D, Groner Y, Crnic LS, Antonarakis S, Mobley W. 2005. Report on the 'Expert Workshop on the Biology of Chromosome 21: towards gene-phenotype correlations in Down syndrome', held June 11-14, 2004, Washington, DC. Cytogenet Genome Res 108:269-277.
Martinez-Cue C, Rueda N, Garcia E, Davisson M, Schmidt C, Florez J. 2005. Behavioral, cognitive and biochemical responses to different environmental conditions in male Ts65Dn mice, a model of Down syndrome. Behav Brain Res 163:174-185.
Pang JJ, Chang B, Hawes NL, Hurd RE, Davisson MT, Li J, Noorwez SM, Malhotra R, McDowell JH, Kaushal S, Hauswirth WW, Nusinowitz S, Thompson DA, Heckenlively JR. 2005. Retinal Degeneration 12 (rd 12): A new spontaneously arising mouse model for human Leber Congenital Amaurosis (LCA). Mol Vis 11:152-162.
Akeson EC, Donahue LR, Beamer WG, Shultz KL, Ackert-Bicknell C, Rosen CJ, Corrigan J, Davisson MT. 2006. Chromosomal inversion discovered in C3H/HeJ mice. Genomics 87:311-313.
Chang B, Heckenlively JR, Bayley PR, Brecha NC, Davisson MT, Hawes NL, Hirano AA, Hurd RE, Ikeda A, Johnson BA, McCall MA, Morgans CW, Nusinowitz S, Peachey NS, Rice DS, Vessey KA, Gregg RG. 2006. The nob2 mouse, a null mutation in Cacna1f: anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses. Vis Neurosci 23:11-24.
Davisson M, Rockwood S. 2006. The benefits of strain donation. Immunity 24(1):3.
Davisson MT, Taft RA. 2006. Strategies for managing an ever increasing mutant mouse repository. Brain Res 1091:255-257.
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.
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.
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.
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.
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.
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.
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. 207. 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.
Note: Other Davisson publications are listed in Davisson, Mouse Mutant Resource: Mouse Models of Human Inherited Diseases report and Chang, Mouse Models of Eye Diseases report.
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.
