Abstract
Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), is challenging to model in mice. Not only is it a contiguous gene syndrome spanning 35 Mb of the long arm of Hsa21, but orthologs of Hsa21 genes map to segments of three mouse chromosomes, Mmu16, Mmu17, and Mmu10. The Ts65Dn was the first viable segmental trisomy mouse model for DS; it is a partial trisomy currently popular in preclinical evaluations of drugs for cognition in DS. Limitations of the Ts65Dn are as follows: (i) it is trisomic for 125 human protein-coding orthologs, but only 90 of these are Hsa21 orthologs and (ii) it lacks trisomy for ~75 Hsa21 orthologs. In recent years, several additional mouse models of DS have been generated, each trisomic for a different subset of Hsa21 genes or their orthologs. To best exploit these models and interpret the results obtained with them, prior to proposing clinical trials, an understanding of their trisomic gene content, relative to full trisomy 21, is necessary. Here we first review the functional information on Hsa21 protein-coding genes and the more recent annotation of a large number of functional RNA genes. We then discuss the conservation and genomic distribution of Hsa21 orthologs in the mouse genome and the distribution of mouse-specific genes. Lastly, we consider the strengths and weaknesses of mouse models of DS based on the number and nature of the Hsa21 orthologs that are, and are not, trisomic in each, and discuss their validity for use in preclinical evaluations of drug responses.
Similar content being viewed by others
References
Ahn KJ, Jeong HK, Choi HS, Ryoo SR, Kim YJ, Goo JS, Choi SY, Han JS, Ha I, Song WJ (2006) DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects. Neurobiol Dis 22:463–472
Al Ahmad A, Lee B, Stack J, Parham C, Campbell J, Clarke D, Fertala A, Bix GJ (2010) Endostatin binds nerve growth factor and thereby inhibits neurite outgrowth and neuronal migration in-vitro. Brain Res 1360:28–39
Alim I, Teves L, Li R, Mori Y, Tymianski M (2013) Modulation of NMDAR subunit expression by TRPM2 channels regulates neuronal vulnerability to ischemic cell death. J Neurosci 33:17264–17277
Andrews SJ, Rothnagel JA (2014) Emerging evidence for functional peptides encoded by short open reading frames. Nat Rev Genet 15:193–204
Antonarakis SE, Lyle R, Dermitzakis ET, Reymond A, Deutsch S (2004) Chromosome 21 and Down syndrome: from genomics to pathophysiology. Nat Rev Genet 5:725–738
Bae JS, Koo NY, Namkoong E, Davies AJ, Choi SK, Shin Y, Jin M, Hwang SM, Mikoshiba K, Park K (2013) Chaperone stress 70 protein (STCH) binds and regulates two acid/base transporters NBCe1-B and NHE1. J Biol Chem 288:6295–6305
Ballarino M, Cazzella V, D’Andrea D, Grassi L, Bisceglie L, Cipriano A, Santini T, Pinnarò C, Morlando M, Tramontano A, Bozzoni I (2015) Novel long noncoding RNAs (lncRNAs) in myogenesis: a miR-31 overlapping lncRNA transcript controls myoblast differentiation. Mol Cell Biol 35:728–736
Bartesaghi R, Haydar TF, Delabar JM, Dierssen M, Martínez-Cué C, Bianchi DW (2015) New perspectives for the rescue of cognitive disability in Down syndrome. J Neurosci 35:13843–13852
Baxter LL, Moran TH, Richtsmeier JT, Troncoso J, Reeves RH (2000) Discovery and genetic localization of Down syndrome cerebellar phenotypes using the Ts65Dn mouse. Hum Mol Genet 9:195–202
Becker W, Soppa U, Tejedor FJ (2014) DYRK1A: a potential drug target for multiple Down syndrome neuropathologies. CNS Neurol Disord Drug Targets 13:26–33
Begley CG, Ellis LM (2012) Drug development: raise standards for preclinical cancer research. Nature 483:531–533
Belichenko PV, Kleschevnikov AM, Becker A, Wagner GE, Lysenko LV, Yu YE, Mobley WC (2015) Down syndrome cognitive phenotypes modeled in mice trisomic for all HSA 21 homologues. PLoS ONE 10:e0134861
Bera TK, Zimonjic DB, Popescu NC, Sathyanarayana BK, Kumar V, Lee B (2002) Pastan I (2002) POTE, a highly homologous gene family located on numerous chromosomes and expressed in prostate, ovary, testis, placenta, and prostate cancer. Proc Natl Acad Sci USA 99:16975–16980
Bergmann JH, Spector DL (2014) Long non-coding RNAs: modulators of nuclear structure and function. Curr Opin Cell Biol 26:10–18
Bialowas-McGoey LA, Lesicka A, Whitaker-Azmitia PM (2008) Vitamin E increases S100B-mediated microglial activation in an S100B-overexpressing mouse model of pathological aging. Glia 56:1780–1790
Block A, Dhanasekaran AR, Ahmed MD, Gardiner KJ (2014) Abnormal protein profiles in hippocampus of mouse models of Down syndrome: similarities with Alzheimer’s Disease. J Alzheimer’s Dis Parkinsonism 4:138–149
Block A, Ahmed MM, Dhanasekaran AR, Tong S, Gardiner KJ (2015) Sex differences in protein expression in the mouse brain and their perturbations in a model of Down syndrome. Biol Sex Differ 6:24
Blythe SA, Cha SW, Tadjuidje E, Heasman J, Klein PS (2010) beta-Catenin primes organizer gene expression by recruiting a histone H3 arginine 8 methyltransferase, Prmt2. Dev Cell 19:220–231
Boada R, Hutaff-Lee C, Schrader A, Weitzenkamp D, Benke TA, Goldson EJ, Costa AC (2012) Antagonism of NMDA receptors as a potential treatment for Down syndrome: a pilot randomized controlled trial. Transl Psychiatry 2:e141
Bofill-De Ros X, Santos M, Vila-Casadesús M, Villanueva E, Andreu N, Dierssen M, Fillat C (2015) Genome-wide miR-155 and miR-802 target gene identification in the hippocampus of Ts65Dn Down syndrome mouse model by miRNA sponges. BMC Genom 16:907
Brault V, Duchon A, Romestaing C, Sahun I, Pothion S, Karout M, Borel C, Dembele D, Bizot JC, Messaddeq N, Sharp AJ, Roussel D, Antonarakis SE, Dierssen M, Hérault Y (2015) Opposite phenotypes of muscle strength and locomotor function in mouse models of partial trisomy and monosomy 21 for the proximal Hspa13-App region. PLoS Genet 11:e1005062
Bruford EA, Lane L, Harrow J (2015) Devising a consensus framework for validation of novel human coding loci. J Proteome Res 14:4945–4948
Canfield MA, Honein MA, Yuskiv N, Xing J, Mai CT, Collins JS, Devine O, Petrini J, Ramadhani TA, Hobbs CA, Kirby RS (2006) National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999-2001. Birth Defects Res A Clin Mol Teratol 76:747–756
Capone GT (2001) Down syndrome: advances in molecular biology and the neurosciences. J Dev Behav Pediatr 22:40–59
Celik O, Nazıroğlu M (2012) Melatonin modulates apoptosis and TRPM2 channels in transfected cells activated by oxidative stress. Physiol Behav 107:458–465
Chapman RS, Hesketh LJ (2000) Behavioral phenotype of individuals with Down syndrome. Ment Retard Dev Disabil Res Rev 6:84–95
Choong XY, Tosh JL, Pulford LJ, Fisher EM (2015) Dissecting Alzheimer disease in Down syndrome using mouse models. Front Behav Neurosci 9:268
Choucair-Jaafar N, Laporte V, Levy R, Poindron P, Lombard Y, Gies JP (2011) Complement receptor 3 (CD11b/CD18) is implicated in the elimination of β-amyloid peptides. Fundam Clin Pharmacol 25:115–122
Cooper A, Grigoryan G, Guy-David L, Tsoory MM, Chen A, Reuveny E (2012) Trisomy of the G protein-coupled K+ channel gene, Kcnj6, affects reward mechanisms, cognitive functions, and synaptic plasticity in mice. Proc Natl Acad Sci U S A. 109:2642–2647
Davisson MT, Schmidt C, Akeson E (1990) Segmental trisomy of murine chromosome 16: a new model system for studying Down syndrome. Prog Clin Biol Res 360:263–280
Davisson MT, Schmidt C, Reeves RH, Irving NG, Akeson EC, Harris BS, Bronson RT (1993) Segmental trisomy as a mouse model for Down syndrome. Prog Clin Biol Res 384:117–133
Davisson MT, Bechtel LJ, Akeson EC, Fortna A, Slavov D, Gardiner K (2001) Evolutionary breakpoints on human chromosome 21. Genomics 78:99–106
de Hoon M, Shin JW, Carninci P (2015) Paradigm shifts in genomics through the FANTOM projects. Mamm Genome 26:391–402
De la Torre R, De Sola S, Pons M, Duchon A, de Lagran MM, Farré M, Fitó M, Benejam B, Langohr K, Rodriguez J, Pujadas M, Bizot JC, Cuenca A, Janel N, Catuara S, Covas MI, Blehaut H, Herault Y, Delabar JM, Dierssen M (2014) Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans. Mol Nutr Food Res 58:278–288
Deininger MH, Fimmen BA, Thal DR, Schluesener HJ, Meyermann R (2002) Aberrant neuronal and paracellular deposition of endostatin in brains of patients with Alzheimer’s disease. J Neurosci 22:10621–10626
Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Knowles DG, Lagarde J, Veeravalli L, Ruan X, Ruan Y, Lassmann T, Carninci P, Brown JB, Lipovich L, Gonzalez JM, Thomas M, Davis CA, Shiekhattar R, Gingeras TR, Hubbard TJ, Notredame C, Harrow J, Guigó R (2012) The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 22:1775–1789
Donato R, Sorci G, Riuzzi F, Arcuri C, Bianchi R, Brozzi F, Tubaro C, Giambanco I (2009) S100B’s double life: intracellular regulator and extracellular signal. Biochim Biophys Acta 1793:1008–1022
Duchon A, Raveau M, Chevalier C, Nalesso V, Sharp AJ, Herault Y (2011) Identification of the translocation breakpoints in the Ts65Dn and Ts1Cje mouse lines: relevance for modeling Down syndrome. Mamm Genome 22:674–684
Duguay D, Bélanger-Nelson E, Mongrain V, Beben A, Khatchadourian A, Cermakian N (2011) Dynein light chain Tctex-type 1 modulates orexin signaling through its interaction with orexin 1 receptor. PLoS One 6:e26430
Emmrich S, Streltsov A, Schmidt F, Thangapandi VR, Reinhardt D, Klusmann JH (2014) LincRNAs MONC and MIR100HG act as oncogenes in acute megakaryoblastic leukemia. Mol Cancer 13:171
Faraoni I, Antonetti FR, Cardone J, Bonmassar E (2009) miR-155 gene: a typical multifunctional microRNA. Biochim Biophys Acta 1792:497–505
Feliciano A, Castellvi J, Artero-Castro A, Leal JA, Romagosa C, Hernández-Losa J, Peg V, Fabra A, Vidal F, Kondoh H, Ramón Y, Cajal S, Lleonart ME (2013) miR-125b acts as a tumor suppressor in breast tumorigenesis via its novel direct targets ENPEP, CK2-α, CCNJ, and MEGF9. PLoS ONE 8:e76247
Flicek P, Amode MR, Barrell D, Beal K, Billis K, Brent S, Carvalho-Silva D, Clapham P, Coates G, Fitzgerald S, Gil L, Girón CG, Gordon L, Hourlier T, Hunt S, Johnson N, Juettemann T, Kähäri AK, Keenan S, Kulesha E, Martin FJ, Maurel T, McLaren WM, Murphy DN, Nag R, Overduin B, Pignatelli M, Pritchard B, Pritchard E, Riat HS, Ruffier M, Sheppard D, Taylor K, Thormann A, Trevanion SJ, Vullo A, Wilder SP, Wilson M, Zadissa A, Aken BL, Birney E, Cunningham F, Harrow J, Herrero J, Hubbard TJ, Kinsella R, Muffato M, Parker A, Spudich G, Yates A, Zerbino DR, Searle SM (2014) Ensembl 2014. Nucleic Acids Res 42:D749–D755
Flynn RA, Chang HY (2014) Long noncoding RNAs in cell-fate programming and reprogramming. Cell Stem Cell 14:752–761
García-Cerro S, Martínez P, Vidal V, Corrales A, Flórez J, Vidal R, Rueda N, Arbonés ML, Martínez-Cué C (2014) Overexpression of Dyrk1A is implicated in several cognitive, electrophysiological and neuromorphological alterations found in a mouse model of Down syndrome. PLoS One 4(9):e106572
Gardiner KJ (2014) Pharmacological approaches to improving cognitive function in Down syndrome: current status and considerations. Drug Des Devel Ther 17:103–125
Gardiner K, Slavov D, Bechtel L, Davisson M (2002) Annotation of human chromosome 21 for relevance to Down syndrome: gene structure and expression analysis. Genomics 79:833–843
Goff LA, Groff AF, Sauvageau M, Trayes-Gibson Z, Sanchez-Gomez DB, Morse M, Martin RD, Elcavage LE, Liapis SC, Gonzalez-Celeiro M, Plana O, Li E, Gerhardinger C, Tomassy GS, Arlotta P, Rinn J (2015) Spatiotemporal expression and transcriptional perturbations by long noncoding RNAs in the mouse brain. Proc Natl Acad Sci USA 112:6855–6862
Goodliffe JW, Olmos-Serrano JL, Aziz NM, Pennings JL, Guedj F, Bianchi DW, Haydar TF (2016) Absence of prenatal forebrain defects in the Dp(16)1Yey/+ Mouse model of Down syndrome. J Neurosci 36:2926–2944
Gray KA, Yates B, Seal RL, Wright MW, Bruford EA (2015) Genenames.org: the HGNC resources in 2015. Nucleic Acids Res 43:D1079–D1085
Gribble SM, Wiseman FK, Clayton S, Prigmore E, Langley E, Yang F, Maguire S, Fu B, Rajan D, Sheppard O, Scott C, Hauser H, Stephens PJ, Stebbings LA, Ng BL, Fitzgerald T, Quail MA, Banerjee R, Rothkamm K, Tybulewicz VL, Fisher EM, Carter NP (2013) Massively parallel sequencing reveals the complex structure of an irradiated human chromosome on a mouse background in the tc1 model of down syndrome. PLoS One 8:e60482
Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, Wang Y, Brzoska P, Kong B, Li R, West RB, van de Vijver MJ, Sukumar S, Chang HY (2010) Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464:1071–1076
Hanney M, Prasher V, Williams N, Jones EL, Aarsland D, Corbett A, Lawrence D, Yu LM, Tyrer S, Francis PT, Johnson T, Bullock R, Ballard C, MEADOWS trial researchers (2012) Memantine for dementia in adults older than 40 years with Down’s syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial. Lancet 379:528–536
Harrow J, Frankish A, Gonzalez JM, Tapanari E, Diekhans M, Kokocinski F, Aken BL, Barrell D, Zadissa A, Searle S, Barnes I, Bignell A, Boychenko V, Hunt T, Kay M, Mukherjee G, Rajan J, Despacio-Reyes G, Saunders G, Steward C, Harte R, Lin M, Howald C, Tanzer A, Derrien T, Chrast J, Walters N, Balasubramanian S, Pei B, Tress M, Rodriguez JM, Ezkurdia I, van Baren J, Brent M, Haussler D, Kellis M, Valencia A, Reymond A, Gerstein M, Guigó R, Hubbard TJ (2012) GENCODE: the reference human genome annotation for The ENCODE Project. Genome Res 22:1760–1774
Harrow JL, Steward CA, Frankish A, Gilbert JG, Gonzalez JM, Loveland JE, Mudge J, Sheppard D, Thomas M, Trevanion S, Wilming LG (2014) The Vertebrate Genome Annotation browser 10 years on. Nucleic Acids Res 42:D771–D779
Hattori M, Fujiyama A, Taylor TD, Watanabe H, Yada T, Park HS, Toyoda A, Ishii K, Totoki Y, Choi DK, Groner Y, Soeda E, Ohki M, Takagi T, Sakaki Y, Taudien S, Blechschmidt K, Polley A, Menzel U, Delabar J, Kumpf K, Lehmann R, Patterson D, Reichwald K, Rump A, Schillhabel M, Schudy A, Zimmermann W, Rosenthal A, Kudoh J, Schibuya K, Kawasaki K, Asakawa S, Shintani A, Sasaki T, Nagamine K, Mitsuyama S, Antonarakis SE, Minoshima S, Shimizu N, Nordsiek G, Hornischer K, Brant P, Scharfe M, Schon O, Desario A, Reichelt J, Kauer G, Blocker H, Ramser J, Beck A, Klages S, Hennig S, Riesselmann L, Dagand E, Haaf T, Wehrmeyer S, Borzym K, Gardiner K, Nizetic D, Francis F, Lehrach H, Reinhardt R, Yaspo ML, Chromosome 21 mapping and sequencing consortium (2000) The DNA sequence of human chromosome 21. Nature 405:311–319
Head E, Lott IT, Wilcock DM, Lemere CA (2016) Aging in Down syndrome and the development of Alzheimer’s disease neuropathology. Curr Alzheimer Res 13:18–29
Hilton JF, Christensen KE, Watkins D, Raby BA, Renaud Y, de la Luna S, Estivill X, MacKenzie RE, Hudson TJ, Rosenblatt DS (2003) The molecular basis of glutamate formiminotransferase deficiency. Hum Mutat 22:67–73
Horsch M, Seeburg PH, Adler T, Aguilar-Pimentel JA, Becker L, Calzada-Wack J, Garrett L, Götz A, Hans W, Higuchi M, Hölter SM, Naton B, Prehn C, Puk O, Rácz I, Rathkolb B, Rozman J, Schrewe A, Adamski J, Busch DH, Esposito I, Graw J, Ivandic B, Klingenspor M, Klopstock T, Mempel M, Ollert M, Schulz H, Wolf E, Wurst W, Zimmer A, Gailus-Durner V, Fuchs H, de Angelis MH, Beckers J (2011) Requirement of the RNA-editing enzyme ADAR2 for normal physiology in mice. J Biol Chem 286:18614–18622
Hutson PH, Finger EN, Magliaro BC, Smith SM, Converso A, Sanderson PE, Mullins D, Hyde LA, Eschle BK, Turnbull Z, Sloan H, Guzzi M, Zhang X, Wang A, Rindgen D, Mazzola R, Vivian JA, Eddins D, Uslaner JM, Bednar R, Gambone C, Le-Mair W, Marino MJ, Sachs N, Xu G, Parmentier-Batteur S (2011) The selective phosphodiesterase 9 (PDE9) inhibitor PF-04447943 (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one) enhances synaptic plasticity and cognitive function in rodents. Neuropharmacology 61:665–676
Hüttenhofer A, Schattner P, Polacek N (2005) Non-coding RNAs: hope or hype? Trends Genet 21:289–297
Irving C, Basu A, Richmond S, Burn J, Wren C (2008) Twenty-year trends in prevalence and survival of Down syndrome. Eur J Hum Genet 16:1336–1340
Iwasaki H, Kovacic JC, Olive M, Beers JK, Yoshimoto T, Crook MF, Tonelli LH, Nabel EG (2010) Disruption of protein arginine N-methyltransferase 2 regulates leptin signaling and produces leanness in vivo through loss of STAT3 methylation. Circ Res 107:992–1001
Jia J, Verma S, Nakayama S, Quillinan N, Grafe MR, Hurn PD, Herson PS (2011) Sex differences in neuroprotection provided by inhibition of TRPM2 channels following experimental stroke. J Cereb Blood Flow Metab 31:2160–2168
Jiang X, Liu C, Yu T, Zhang L, Meng K, Xing Z, Belichenko PV, Kleschevnikov AM, Pao A, Peresie J, Wie S, Mobley WC, Yu YE (2015) Genetic dissection of the Down syndrome critical region. Hum Mol Genet 24:6540–6551
Kido S, Sakuragi N, Bronner MP, Sayegh R, Berger R, Patterson D, Strauss JF 3rd (1993) D21S418E identifies a cAMP-regulated gene located on chromosome 21q22.3 that is expressed in placental syncytiotrophoblast and choriocarcinoma cells. Genomics 17:256–259
Korbel JO, Tirosh-Wagner T, Urban AE, Chen XN, Kasowski M, Dai L, Grubert F, Erdman C, Gao MC, Lange K, Sobel EM, Barlow GM, Aylsworth AS, Carpenter NJ, Clark RD, Cohen MY, Doran E, Falik-Zaccai T, Lewin SO, Lott IT, McGillivray BC, Moeschler JB, Pettenati MJ, Pueschel SM, Rao KW, Shaffer LG, Shohat M, Van Riper AJ, Warburton D, Weissman S, Gerstein MB, Snyder M, Korenberg JR (2009) The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies. Proc Natl Acad Sci USA 106:12031–12036
Korenberg JR, Chen XN, Schipper R, Sun Z, Gonsky R, Gerwehr S, Carpenter N, Daumer C, Dignan P, Disteche C, Graham JM Jr, Hugdins L, Mcgillivray B, Miyazaki K, Ogasawara N, Park JP, Pagon R, Pueschel S, Sack G, Say B, Schuffenhauer S, Soukup S, Yamanaka T (1994) Down syndrome phenotypes: the consequences of chromosomal imbalance. Proc Natl Acad Sci USA 91:4997–5001
Kroker KS, Rast G, Giovannini R, Marti A, Dorner-Ciossek C, Rosenbrock H (2012) Inhibition of acetylcholinesterase and phosphodiesterase-9A has differential effects on hippocampal early and late LTP. Neuropharmacology 62:1964–1974
Kuehn BM (2016) Treating trisomies: prenatal Down’s syndrome therapies explored in mice. Nat Med 22:6–7
Lawrie CH (2013) MicroRNAs and lymphomagenesis: a functional review. Br J Haematol 160:571–581
Li L, Chang HY (2014) Physiological roles of long noncoding RNAs: insight from knockout mice. Trends Cell Biol 24:594–602
Li Y, Wang H, Wang S, Quon D, Liu YW, Cordell B (2003) Positive and negative regulation of APP amyloidogenesis by sumoylation. Proc Natl Acad Sci USA 100:259–264
Li Z, Yu T, Morishima M, Pao A, LaDuca J, Conroy J, Nowak N, Matsui S, Shiraishi I, Yu YE (2007) Duplication of the entire 22.9 Mb human chromosome 21 syntenic region on mouse chromosome 16 causes cardiovascular and gastrointestinal abnormalities. Hum Mol Genet 16:1359–1366
Li W, Notani D, Ma Q, Tanasa B, Nunez E, Chen AY, Merkurjev D, Zhang J, Ohgi K, Song X, Oh S, Kim HS, Glass CK, Rosenfeld MG (2013) Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498:516–520
Liu Z, Long X, Chao C, Yan C, Wu Q, Hua S, Zhang Y, Wu A, Fang W (2014) Knocking down CDK4 mediates the elevation of let-7c suppressing cell growth in nasopharyngeal carcinoma. BMC Cancer 14:274
Lopez-Pajares V, Qu K, Zhang J, Webster DE, Barajas BC, Siprashvili Z, Zarnegar BJ, Boxer LD, Rios EJ, Tao S, Kretz M, Khavari PA (2015) A LncRNA-MAF:MAFB transcription factor network regulates epidermal differentiation. Dev Cell 32:693–706
Lott IT, Doran E, Nguyen VQ, Tournay A, Head E, Gillen DL (2011) Down syndrome and dementia: a randomized, controlled trial of antioxidant supplementation. Am J Med Genet A 155A:1939–1948
Louro R, Smirnova AS, Verjovski-Almeida S (2009) Long intronic noncoding RNA transcription: expression noise or expression choice? Genomics 93:291–298
Lu J, Esposito G, Scuderi C, Steardo L, Delli-Bovi LC, Hecht JL, Dickinson BC, Chang CJ, Mori T, Sheen V (2011) S100B and APP promote a gliocentric shift and impaired neurogenesis in Down syndrome neural progenitors. PLoS One 6:e22126
Ma MP, Robinson PJ, Chircop M (2013) Sorting nexin 9 recruits clathrin heavy chain to the mitotic spindle for chromosome alignment and segregation. PLoS One 8:e68387
Macleod MR (2014) Preclinical research: design animal studies better. Nature 510:35
Mattick JS (2003) Challenging the dogma: the hidden layer of non-protein-coding RNAs in complex organisms. BioEssays 25:930–939
Mattick JS, Makunin IV (2006) Non-coding RNA. Hum Mol Genet 15(1):R17–29
McGonigle P (2014) Animal models of CNS disorders. Biochem Pharmacol 87:140–149
McGonigle P, Ruggeri B (2014) Animal models of human disease: challenges in enabling translation. Biochem Pharmacol 87:162–171
Mercer TR, Dinger ME, Mattick JS (2009) Long non-coding RNAs: insights into functions. Nat Rev Genet 10:155–159
Meyer R, Wolf SS, Obendorf M (2007) PRMT2, a member of the protein arginine methyltransferase family, is a coactivator of the androgen receptor. J Steroid Biochem Mol Biol 107:1–14
Moore CS, Hawkins C, Franca A, Lawler A, Devenney B, Das I, Reeves RH (2010) Increased male reproductive success in Ts65Dn “Down syndrome” mice. Mamm Genome 21:543–549
Mori T, Koyama N, Arendash GW, Horikoshi-Sakuraba Y, Tan J, Town T (2010) Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer’s disease. Glia 58:300–314
Nakamura A, Hattori M, Sakaki Y (1997) A novel gene isolated from human placenta located in Down syndrome critical region on chromosome 21. DNA Res 4:321–324
Nelson DL, Gibbs RA (2004) Genetics. The critical region in trisomy 21. Science 306:619–621
Ng SY, Bogu GK, Soh BS, Stanton LW (2013) The long noncoding RNA RMST interacts with SOX2 to regulate neurogenesis. Mol Cell 51:349–359
O’Doherty A, Ruf S, Mulligan C, Hildreth V, Errington ML, Cooke S, Sesay A, Modino S, Vanes L, Hernandez D, Linehan JM, Sharpe PT, Brandner S, Bliss TV, Henderson DJ, Nizetic D, Tybulewicz VL, Fisher EM (2005) An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes. Science 309:2033–2037
O’Leary NA, Wright MW, Brister JR, Ciufo S, Haddad D, McVeigh R, Rajput B, Robbertse B, Smith-White B, Ako-Adjei D, Astashyn A, Badretdin A, Bao Y, Blinkova O, Brover V, Chetvernin V, Choi J, Cox E, Ermolaeva O, Farrell CM, Goldfarb T, Gupta T, Haft D, Hatcher E, Hlavina W, Joardar VS, Kodali VK, Li W, Maglott D, Masterson P, McGarvey KM, Murphy MR, O’Neill K, Pujar S, Rangwala SH, Rausch D, Riddick LD, Schoch C, Shkeda A, Storz SS, Sun H, Thibaud-Nissen F, Tolstoy I, Tully RE, Vatsan AR, Wallin C, Webb D, Wu W, Landrum MJ, Kimchi A, Tatusova T, DiCuccio M, Kitts P, Murphy TD, Pruitt KD (2016) Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation. Nucleic Acids Res 44:D733–D745
Olson LE, Richtsmeier JT, Leszl J, Reeves RH (2004) A chromosome 21 critical region does not cause specific Down syndrome phenotypes. Science 306:687–690
Olson LE, Roper RJ, Sengstaken CL, Peterson EA, Aquino V, Galdzicki Z, Siarey R, Pletnikov M, Moran TH, Reeves RH (2007) Trisomy for the Down syndrome ‘critical region’ is necessary but not sufficient for brain phenotypes of trisomic mice. Hum Mol Genet 16:774–782
Pereira PL, Magnol L, Sahún I, Brault V, Duchon A, Prandini P, Gruart A, Bizot JC, Chadefaux-Vekemans B, Deutsch S, Trovero F, Delgado-García JM, Antonarakis SE, Dierssen M, Herault Y (2009) A new mouse model for the trisomy of the Abcg1-U2af1 region reveals the complexity of the combinatorial genetic code of down syndrome. Hum Mol Genet 18:4756–4769
Perrin S (2014) Preclinical research: make mouse studies work. Nature 507:423–425
Petit F, Plessis G, Decamp M, Cuisset JM, Blyth M, Pendlebury M, Andrieux J (2015) 21q21 deletion involving NCAM2: report of 3 cases with neurodevelopmental disorders. Eur J Med Genet 58:44–46
Qi C, Chang J, Zhu Y, Yeldandi AV, Rao SM, Zhu YJ (2002) Identification of protein arginine methyltransferase 2 as a coactivator for estrogen receptor alpha. J Biol Chem 277:28624–28630
Quiñones-Lombraña A, Blanco JG (2015) Chromosome 21-derived hsa-miR-155-5p regulates mitochondrial biogenesis by targeting Mitochondrial Transcription Factor A (TFAM). Biochim Biophys Acta 1852:1420–1427
Rahmani Z, Blouin JL, Créau-Goldberg N, Watkins PC, Mattei JF, Poissonnier M, Prieur M, Chettouh Z, Nicole A, Aurias A et al (1990) Down syndrome critical region around D21S55 on proximal 21q22.3. Am J Med Genet Suppl 7:98–103
Ramos AD, Attenello FJ, Lim DA (2015) Uncovering the roles of long noncoding RNAs in neural development and glioma progression. Neurosci Lett S0304–3940:30316-5
Reeves R, Irving N, Moran T, Wohn A, Kitt C, Sisodia S, Schmidt C, Bronson R, Davisson MT (1995) A mouse model for Down Syndrome exhibits learning and behaviour deficits. Nat Genet 11:177–184
Rogers MA, Langbein L, Winter H, Ehmann C, Praetzel S, Schweizer J (2002) Characterization of a first domain of human high glycine-tyrosine and high sulfur keratin-associated protein (KAP) genes on chromosome 21q22.1. J Biol Chem 277:48993–49002
Rogers MA, Langbein L, Praetzel-Wunder S, Winter H, Schweizer J (2006) Human hair keratin-associated proteins (KAPs). Int Rev Cytol 251:209–263
Rosenbloom KR, Sloan CA, Malladi VS, Dreszer TR, Learned K, Kirkup VM, Wong MC, Maddren M, Fang R, Heitner SG, Lee BT, Barber GP, Harte RA, Diekhans M, Long JC, Wilder SP, Zweig AS, Karolchik D, Kuhn RM, Haussler D, Kent WJ (2013) ENCODE data in the UCSC Genome Browser: year 5 update. Nucleic Acids Res 41:D56–D63
Rueda N, Flórez J, Martínez-Cué C (2012) Mouse models of Down syndrome as a tool to unravel the causes of mental disabilities. Neural Plast 2012:584071
Saghatelian A, Couso JP (2015) Discovery and characterization of smORF-encoded bioactive polypeptides. Nat Chem Biol 11:909–916
Sago H, Carlson EJ, Smith DJ, Kilbridge J, Rubin EM, Mobley WC, Epstein CJ, Huang TT (1998) Ts1Cje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities. Proc Natl Acad Sci USA. 95:6256–6261
Salehi A, Delcroix JD, Belichenko PV, Zhan K, Wu C, Valletta JS, Takimoto-Kimura R, Kleschevnikov AM, Sambamurti K, Chung PP, Xia W, Villar A, Campbell WA, Kulnane LS, Nixon RA, Lamb BT, Epstein CJ, Stokin GB, Goldstein LS, Mobley WC (2006) Increased App expression in a mouse model of Down’s syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron 51:29–42
Sauvageau M, Goff LA, Lodato S, Bonev B, Groff AF, Gerhardinger C, Sanchez-Gomez DB, Hacisuleyman E, Li E, Spence M, Liapis SC, Mallard W, Morse M, Swerdel MR, D’Ecclessis MF, Moore JC, Lai V, Gong G, Yancopoulos GD, Frendewey D, Kellis M, Hart RP, Valenzuela DM, Arlotta P, Rinn JL (2013) Multiple knockout mouse models reveal lincRNAs are required for life and brain development. Elife 2:e01749
Shi HS, Yin X, Song L, Guo QJ, Luo XH (2012) Neuropeptide Trefoil factor 3 improves learning and retention of novel object recognition memory in mice. Behav Brain Res 227:265–269
Shin N, Lee S, Ahn N, Kim SA, Ahn SG, YongPark Z, Chang S (2007) Sorting nexin 9 interacts with dynamin 1 and N-WASP and coordinates synaptic vesicle endocytosis. J Biol Chem 282:28939–28950
Siarey RJ, Villar AJ, Epstein CJ, Galdzicki Z (2005) Abnormal synaptic plasticity in the Ts1Cje segmental trisomy 16 mouse model of Down syndrome. Neuropharmacology 49:122–128
Smith CM, Steitz JA (1998) Classification of gas5 as a multi-small-nucleolar-RNA (snoRNA) host gene and a member of the 5′-terminal oligopyrimidine gene family reveals common features of snoRNA host genes. Mol Cell Biol 18:6897–6909
Song J, Lee JE (2015) miR-155 is involved in Alzheimer’s disease by regulating T lymphocyte function. Front Aging Neurosci 7:61
Souchet B, Guedj F, Penke-Verdier Z, Daubigney F, Duchon A, Herault Y, Bizot JC, Janel N, Créau N, Delatour B, Delabar JM (2015) Pharmacological correction of excitation/inhibition imbalance in Down syndrome mouse models. Front Behav Neurosci 9:267
Starbuck JM, Dutka T, Ratliff TS, Reeves RH, Richtsmeier JT (2014) Overlapping trisomies for human chromosome 21 orthologs produce similar effects on skull and brain morphology of Dp(16)1Yey and Ts65Dn mice. Am J Med Genet A 164A:1981–1990
Sturgeon X, Gardiner KJ (2011) Transcript catalogs of human chromosome 21 and orthologous chimpanzee and mouse regions. Mamm Genome 22:261–271
Sturgeon X, Le T, Ahmed MM, Gardiner KJ (2012) Pathways to cognitive deficits in Down syndrome. Prog Brain Res 197:73–100
Su X, Zhu G, Ding X, Lee SY, Dou Y, Zhu B, Wu W, Li H (2014) Molecular basis underlying histone H3 lysine-arginine methylation pattern readout by Spin/Ssty repeats of Spindlin1. Genes Dev 28:622–636
Tomaselli S, Bonamassa B, Alisi A, Nobili V, Locatelli F, Gallo A (2013) ADAR enzyme and miRNA story: a nucleotide that can make the difference. Int J Mol Sci 14:22796–22816
Vance KW, Ponting CP (2014) Transcriptional regulatory functions of nuclear long noncoding RNAs. Trends Genet 30:348–355
Verma S, Quillinan N, Yang YF, Nakayama S, Cheng J, Kelley MH, Herson PS (2012) TRPM2 channel activation following in vitro ischemia contributes to male hippocampal cell death. Neurosci Lett 530:41–46
Vidal V, García S, Martínez P, Corrales A, Flórez J, Rueda N, Sharma A, Martínez-Cué C (2012) Lack of behavioral and cognitive effects of chronic ethosuximide and gabapentin treatment in the Ts65Dn mouse model of Down syndrome. Neuroscience 220:158–168
Warth SC, Hoefig KP, Hiekel A, Schallenberg S, Jovanovic K, Klein L, Kretschmer K, Ansel KM, Heissmeyer V (2015) Induced miR-99a expression represses Mtor cooperatively with miR-150 to promote regulatory T-cell differentiation. EMBO J 34:1195–1213
White R, Morganstein D, Christian M, Seth A, Herzog B, Parker MG (2008) Role of RIP140 in metabolic tissues: connections to disease. FEBS Lett 582:39–45
Winkler GS (2010) The mammalian anti-proliferative BTG/Tob protein family. J Cell Physiol 222:66–72
Winocur G, Roder J, Lobaugh N (2001) Learning and memory in S100-beta transgenic mice: an analysis of impaired and preserved function. Neurobiol Learn Mem 75:230–243
Winther M, Berezin V, Walmod PS (2012) NCAM2/OCAM/RNCAM: cell adhesion molecule with a role in neuronal compartmentalization. Int J Biochem Cell Biol 44:441–446
Worby CA, Simonson-Leff N, Clemens JC, Kruger RP, Muda M, Dixon JE (2001) The sorting nexin, DSH3PX1, connects the axonal guidance receptor, Dscam, to the actin cytoskeleton. J Biol Chem 276:41782–41789
Wu N, Lin X, Zhao X, Zheng L, Xiao L, Liu J, Ge L, Cao S (2013) MiR-125b acts as an oncogene in glioblastoma cells and inhibits cell apoptosis through p53 and p38MAPK-independent pathways. Br J Cancer 109:2853–2863
Wu D, Zhou Y, Pan H, Qu P, Zhou J (2015) microRNA 99a inhibits cell proliferation, colony formation ability, migration and invasion by targeting fibroblast growth factor receptor 3 in prostate cancer. Mol Med Rep. 11:1469–1475
Xie YF, Belrose JC, Lei G, Tymianski M, Mori Y, Macdonald JF, Jackson MF (2011) Dependence of NMDA/GSK-3β mediated metaplasticity on TRPM2 channels at hippocampal CA3-CA1 synapses. Mol Brain 4:44
Xu Y, Zhang HT, O’Donnell JM (2011) Phosphodiesterases in the central nervous system: implications in mood and cognitive disorders. Handb Exp Pharmacol 204:447–485
Yang DS, Stavrides P, Mohan PS, Kaushik S, Kumar A, Ohno M, Schmidt SD, Wesson DW, Bandyopadhyay U, Jiang Y, Pawlik M, Peterhoff CM, Yang AJ, Wilson DA, St George-Hyslop P, Westaway D, Mathews PM, Levy E, Cuervo AM, Nixon RA (2011) Therapeutic effects of remediating autophagy failure in a mouse model of Alzheimer disease by enhancing lysosomal proteolysis. Autophagy 7:788–789
Yang QG, Wang F, Zhang Q, Xu WR, Chen YP, Chen GH (2012) Correlation of increased hippocampal Sumo3 with spatial learning ability in old C57BL/6 mice. Neurosci Lett 518:75–79
Yang Z, Han Y, Cheng K, Zhang G, Wang X (2014) miR-99a directly targets the mTOR signalling pathway in breast cancer side population cells. Cell Prolif 47:587–595
Yu X, Li Z (2015) Long non-coding RNA growth arrest-specific transcript 5 in tumor biology. Oncol Lett 10:1953–1958
Yu H et al (2005) TCP10L is expressed specifically in spermatogenic cells and binds to death associated protein kinase-3. Int J Androl 28:163–170
Yu T, Li Z, Jia Z, Clapcote SJ, Liu C, Li S, Asrar S, Pao A, Chen R, Fan N, Carattini-Rivera S, Bechard AR, Spring S, Henkelman RM, Stoica G, Matsui S, Nowak NJ, Roder JC, Chen C, Bradley A, Yu YE (2010a) A mouse model of Down syndrome trisomic for all human chromosome 21 syntenic regions. Hum Mol Genet 19:2780–2791
Yu T, Liu C, Belichenko P, Clapcote SJ, Li S, Pao A, Kleschevnikov A, Bechard AR, Asrar S, Chen R, Fan N, Zhou Z, Jia Z, Chen C, Roder JC, Liu B, Baldini A, Mobley WC, Yu YE (2010b) Effects of individual segmental trisomies of human chromosome 21 syntenic regions on hippocampal long-term potentiation and cognitive behaviors in mice. Brain Res 1366:162–171
Yu SH, Zhang CL, Dong FS, Zhang YM (2015) miR-99a suppresses the metastasis of human non-small cell lung cancer cells by targeting AKT1 signaling pathway. J Cell Biochem 116:268–276
Zenaro E, Pietronigro E, Bianca VD, Piacentino G, Marongiu L, Budui S, Turano E, Rossi B, Angiari S, Dusi S, Montresor A, Carlucci T, Nanì S, Tosadori G, Calciano L, Catalucci D, Berton G, Bonetti B, Constantin G (2015) Neutrophils promote Alzheimer’s disease-like pathology and cognitive decline via LFA-1 integrin. Nat Med 21:880–886
Zhang L, Meng K, Jiang X, Liu C, Pao A, Belichenko PV, Kleschevnikov AM, Josselyn S, Liang P, Ye P, Mobley WC, Yu YE (2014) Human chromosome 21 orthologous region on mouse chromosome 17 is a major determinant of Down syndrome-related developmental cognitive deficits. Hum Mol Genet 23:578–589
Zhao B, Han H, Chen J, Zhang Z, Li S, Fang F, Zheng Q, Ma Y, Zhang J, Wu N, Yang Y (2014) MicroRNA let-7c inhibits migration and invasion of human non-small cell lung cancer by targeting ITGB3 and MAP4K3. Cancer Lett 342:43–51
Zheng Z, Cai C, Omwancha J, Chen S-Y, Baslan T, Shemshedini L (2006) SUMO-3 enhances androgen receptor transcriptional activity through a sumoylation-independent mechanism in prostate cancer cells. J Biol Chem 281:4002–4012
Zhou B, Cai Q, Xie Y, Sheng ZH (2012) Snapin recruits dynein to BDNF-TrkB signaling endosomes for retrograde axonal transport and is essential for dendrite growth of cortical neurons. Cell Rep 2:42–51
Acknowledgments
This work was supported by the National Institute of Child Health and Human Development (HD071585) and the Linda Crnic Institute for Down Syndrome.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Gupta, M., Dhanasekaran, A.R. & Gardiner, K.J. Mouse models of Down syndrome: gene content and consequences. Mamm Genome 27, 538–555 (2016). https://doi.org/10.1007/s00335-016-9661-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00335-016-9661-8