Species: Mouse
Modification: Multi-transgene
Disease Relevance: Down's Syndrome, Alzheimer's Disease
Strain Name: B6.129S7-Dp(16Lipi-Zbtb21)1Yey/J
Genetic Background: C57BL/6J
Availability: Available from The Jackson Lab: Strain 013530.

Summary

The Dp(16)1Yey/+ mouse model has an extra copy of approximately 65 percent of the mouse genes on chromosome 16 that are orthologous to genes on human chromosome 21 (Hsa21) (Li et al., 2007). Mutant mice are fertile. This duplicated region has been implicated in developmental cognitive disabilities and early onset Alzheimer’s disease (AD) associated with Down Syndrome (DS).

AD-associated neuropathology

The triplication of the App gene contributes to loss of vulnerable neurons: neurons in layer II of entorhinal cortex, and catecholaminergic neurons in the locus coeruleus and the basal forebrain magnocellular complex. It also results in tau pathology and an increase in astrocyte and microglia numbers at 13-19 months of age (Chen et al., 2023; Sawa et al., 2022).

Behavioral/Neurological Phenotypes

Dp(16)1Yey/+ mice show deficits in motor coordination. In the Rotarod test, the mice fell significantly faster than controls at 3 to 7 months of age (Aziz et al., 2018). In addition, the mice suffer from several behavioral alterations. Dp(16)1Yey/+ mice exhibit deficits in contextual fear conditioning, indicative of contextual memory impairment, impaired spatial learning in the Morris water maze, impaired novel object recognition memory, and impairments in spontaneous alternation in the T-maze at 1 to 7 months of age (Aziz et al., 2018; Jiang et al., 2015; Patel et al., 2015; Pinto et al., 2020; Raveau et al., 2018; Yu et al., 2010). Also, the magnitude of hippocampal long-term potentiation following theta burst stimulation is lower than in wildtype controls around 2 to 4 months of age. 

Moreover, aged Dp(16)1Yey/+ mice spend longer times awake during the dark and light cycles and have reduced non-rapid eye movement (NREM) sleep, indicative of impairment in sleeping behavior at 12 to 14 months of age (Levenga et al., 2018). Dp(16)1Yey/+ mice also exhibit differences in ultrasonic vocalization compared to control mice at 5 months of age (Glass et al., 2023). 

Other Phenotypes

The chromosomal duplication of Dp(16)1Yey/1 mice also results in multiple non-neurological phenotypes. For example, these animals exhibit several heart abnormalities, including perimembranous ventricular septal defects, overriding of the aorta, narrowed outflow track of the right ventricle, ventricle septal defects, atrial septal defects, cleft mitral valves, severe coarctation of the aorta and double outlet right ventricle at the embryonic day E18.5 (Li et al., 2007). Mutant mice also develop pulmonary abnormalities at 9 to13 weeks of age (Colvin et al., 2023).

In addition, Dp(16)1Yey/+ mice suffer from immune and blood cell alterations. They exhibit hyperactive IFN signaling and associated phenotypic alterations at 3 to 9 months of age (Sullivan et al., 2016; Waugh et al., 2023), as well as myeloproliferative disorder at 3-15 months of age (Liu et al., 2018).

Also of note, Dp(16)1Yey/+ mice have larger cranial vault measurements along the mediolateral and rostrocaudal axes. Frontal, nasal, premaxillary, and palatine bones exhibit smaller dimensions along dorsoventral, mediolateral, and rostrocaudal axes. Presphenoid and basisphenoids exhibit smaller size along the rostrocaudal and mediolateral axes as well as a smaller mandible along the dorsoventral and mediolateral axes (Starbuck et al., 2014). Moreover, middle ear anomalies have been detected at 3 to 9 months of age, together with hearing impairment (Chen et al., 2022). Dp(16)1Yey/+ mice also have reduced bone mass,  as well as significant impairment in fracture healing  at 6 weeks of age and at 3 months of age or older, and these alterations were sexually dimorphic (Sherman et al., 2022; Lamantia et al., 2024).

Metabolic abnormalities have also been reported in Dp(16)1Yey/+ mice, including hyperglycemia  at 3-5 months of age (Peiris et al., 2016).

Moreover, mutant male mice showed impairments related to spermatogenesis at 3 months of age (Dard et al., 2023).

Modification details

A 22.9Mb duplication extending from the lipase member I (Lipi) gene to the Zinc Finger and BTB Domain Containing 21 protein gene (Zbtb21) on mouse chromosome 16 was generated in mouse ES cells using Cre/loxP-mediated chromosome engineering (Li et al., 2007). The desired ES cell clones were injected into C57BL/6J-Tyrc-Brd blastocysts to generate chimeric mice, and these were bred to establish the B6.129S7-Dp(16Lipi-Zbtb21)1Yey/J (Dp(16)1Yey/+) mouse strain. The duplicated region includes 115 genes, including App, which are orthologous to human chromosome 21 (Hsa21), covering about 65 percent of the chromosome.

This summary was prepared by the Trisomy 21 Research Society.

Related Models
The following are additional Down syndrome models carrying either a Cre/lox-generated partial duplication of mouse chromosome 16 (the ortholog of human chromosome 21, Hsa21), a hybrid chromosome containing segments of mouse chromosomes 16 and 17 generated by irradiation, or the long arm of Hsa21 in a mouse artificial chromosome:

Ts65Dn. These mice have been extensively studied as a Down syndrome mouse model. The line is aneuploid carrying a freely segregating, supernumerary chromosome generated by irradiation. The extra chromosome harbors a piece of mouse chromosome 16, including App, fused with a piece of mouse chromosome 17. These mice display elevated levels of full-length murine App and its derivatives, including Aβ40 and Aβ42, but no plaque pathology. Moreover, Ts65Dn mice show increased tau expression and altered 3R/4R tau mRNA splicing. They also have multiple neuropathological changes and age-related behavioral alterations akin to Down syndrome AD. Ts65Dn mice also exhibit a range of peripheral physical and physiological DS-like deficits.

Dp1Tyb. These mice have an extra copy of approximately 65 percent of the mouse genes on chromosome 16, including App, generated by Cre/lox engineering. They have neurodevelopmental alterations resulting in reduced medial prefrontal cortex and dorsal hippocampus volumes, reduced density of neurons, and increased density of microglia in the hippocampus. Spatial working memory, exploratory behavior, and fear memory are impaired, as well as motor function and sleep architecture. Heart, lung, hematologic, skeletal, ear, and metabolic abnormalities similar to those associated with Down syndrome have been reported.

Dp9Tyb. These mice carry a duplication of mouse chromosome 16 generated by Cre/lox engineering that spans a segment between the Lipi and Hunk genes, including App. The duplication lacks some genes suspected to be relevant to Down syndrome-associated AD, such as Dyrk1a and Bace2. Dp9Tyb mice have not yet been well characterized.

TcMAC21. This mouse model contains a nearly complete and freely segregating long arm of Hsa21 (including the APP gene) in the form of a hybrid mouse artificial chromosome, with no detectable mosaicism in a broad spectrum of tissues and cell types. TcMAC21 recapitulates many Down syndrome phenotypes including deficits in learning, memory and synaptic plasticity, anomalies in heart, craniofacial skeleton and brain development, and molecular/cellular alterations. Elevated levels of APP and its cleavage products, Aβ40 and Aβ42, have been observed in the TcMAC21 model at 15–24 months of age, but amyloid plaque pathology has not been detected.

Phenotype Characterization

Q&A with Model Creator

Q&A with expert Eugene Yu

What would you say are the unique advantages of this model?
The Dp(16)1Yey/+ model exhibits a significant number of phenotypic alterations related to Down syndrome, effectively recapitulating the complex co-morbidities which occur in individuals who have Down syndrome.

What do you think this model is best used for?
The model is particularly useful for studying neuronal degeneration associated with Alzheimer’s disease in Down syndrome, cognitive deficits, and immune dysregulation.

What caveats are associated with this model?
Caveats include the lack of triplication of some Hsa21 gene orthologs, absence of an extra chromosome, and absence of amyloid-β plaque pathology.

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References

Research Models Citations

1. Ts65Dn
2. Dp1Tyb
3. Dp9Tyb
4. TcMAC21

Paper Citations

1. Li Z, Yu T, Morishima M, Pao A, LaDuca J, Conroy J, Nowak N, Matsui S, Shiraishi I, Yu YE. Duplication of the entire 22.9 Mb human chromosome 21 syntenic region on mouse chromosome 16 causes cardiovascular and gastrointestinal abnormalities. Hum Mol Genet. 2007 Jun 1;16(11):1359-66. Epub 2007 Apr 5 PubMed.
2. Chen XQ, Zuo X, Becker A, Head E, Mobley WC. Reduced synaptic proteins and SNARE complexes in Down syndrome with Alzheimer's disease and the Dp16 mouse Down syndrome model: Impact of APP gene dose. Alzheimers Dement. 2023 May;19(5):2095-2116. Epub 2022 Nov 12 PubMed.
3. Sawa M, Overk C, Becker A, Derse D, Albay R, Weldy K, Salehi A, Beach TG, Doran E, Head E, Yu YE, Mobley WC. Impact of increased APP gene dose in Down syndrome and the Dp16 mouse model. Alzheimers Dement. 2022 Jun;18(6):1203-1234. Epub 2021 Nov 10 PubMed.
4. Aziz NM, Guedj F, Pennings JL, Olmos-Serrano JL, Siegel A, Haydar TF, Bianchi DW. Lifespan analysis of brain development, gene expression and behavioral phenotypes in the Ts1Cje, Ts65Dn and Dp(16)1/Yey mouse models of Down syndrome. Dis Model Mech. 2018 Jun 12;11(6) PubMed.
5. 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. Genetic dissection of the Down syndrome critical region. Hum Mol Genet. 2015 Nov 15;24(22):6540-51. Epub 2015 Sep 15 PubMed.
6. Patel A, Yamashita N, Ascaño M, Bodmer D, Boehm E, Bodkin-Clarke C, Ryu YK, Kuruvilla R. RCAN1 links impaired neurotrophin trafficking to aberrant development of the sympathetic nervous system in Down syndrome. Nat Commun. 2015 Dec 14;6:10119. PubMed.
7. Pinto B, Morelli G, Rastogi M, Savardi A, Fumagalli A, Petretto A, Bartolucci M, Varea E, Catelani T, Contestabile A, Perlini LE, Cancedda L. Rescuing Over-activated Microglia Restores Cognitive Performance in Juvenile Animals of the Dp(16) Mouse Model of Down Syndrome. Neuron. 2020 Dec 9;108(5):887-904.e12. Epub 2020 Oct 6 PubMed.
8. Raveau M, Polygalov D, Boehringer R, Amano K, Yamakawa K, McHugh TJ. Alterations of in vivo CA1 network activity in Dp(16)1Yey Down syndrome model mice. Elife. 2018 Feb 27;7 PubMed.
9. 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. Effects of individual segmental trisomies of human chromosome 21 syntenic regions on hippocampal long-term potentiation and cognitive behaviors in mice. Brain Res. 2010 Dec 17;1366:162-71. Epub 2010 Oct 26 PubMed.
10. Lamantia J, Sloan K, Wallace JM, Roper RJ. Compromised femoral and lumbovertebral bone in the Dp(16)1Yey Down syndrome mouse model. Bone. 2024 Apr;181:117046. Epub 2024 Feb 7 PubMed.
11. Glass TJ, Lenell C, Fisher EH, Yang Q, Connor NP. Ultrasonic vocalization phenotypes in the Ts65Dn and Dp(16)1Yey mouse models of Down syndrome. Physiol Behav. 2023 Nov 1;271:114323. Epub 2023 Aug 11 PubMed.
12. Colvin KL, Nguyen K, Boncella KL, Goodman DM, Elliott RJ, Harral JW, Bilodeaux J, Smith BJ, Yeager ME. Lung and Heart Biology of the Dp16 Mouse Model of down Syndrome: Implications for Studying Cardiopulmonary Disease. Genes (Basel). 2023 Sep 19;14(9) PubMed.
13. Sullivan KD, Lewis HC, Hill AA, Pandey A, Jackson LP, Cabral JM, Smith KP, Liggett LA, Gomez EB, Galbraith MD, DeGregori J, Espinosa JM. Trisomy 21 consistently activates the interferon response. Elife. 2016 Jul 29;5 PubMed.
14. Waugh KA, Minter R, Baxter J, Chi C, Galbraith MD, Tuttle KD, Eduthan NP, Kinning KT, Andrysik Z, Araya P, Dougherty H, Dunn LN, Ludwig M, Schade KA, Tracy D, Smith KP, Granrath RE, Busquet N, Khanal S, Anderson RD, Cox LL, Estrada BE, Rachubinski AL, Lyford HR, Britton EC, Fantauzzo KA, Orlicky DJ, Matsuda JL, Song K, Cox TC, Sullivan KD, Espinosa JM. Triplication of the interferon receptor locus contributes to hallmarks of Down syndrome in a mouse model. Nat Genet. 2023 Jun;55(6):1034-1047. Epub 2023 Jun 5 PubMed.
15. Liu C, Yu T, Xing Z, Jiang X, Li Y, Pao A, Mu J, Wallace PK, Stoica G, Bakin AV, Yu YE. Triplications of human chromosome 21 orthologous regions in mice result in expansion of megakaryocyte-erythroid progenitors and reduction of granulocyte-macrophage progenitors. Oncotarget. 2018 Jan 12;9(4):4773-4786. Epub 2017 Dec 19 PubMed.
16. Starbuck JM, Dutka T, Ratliff TS, Reeves RH, Richtsmeier JT. 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. 2014 Aug;164A(8):1981-1990. Epub 2014 May 1 PubMed.
17. Chen GD, Li L, McCall A, Ding D, Xing Z, Yu YE, Salvi R. Hearing impairment in murine model of Down syndrome. Front Genet. 2022;13:936128. Epub 2022 Aug 4 PubMed.
18. Sherman KM, Williams DK, Welsh CA, Cooper AM, Falck A, Huggins S, Bokhari RS, Gaddy D, McKelvey KD, Dawson LA, Suva LJ. Low bone mass and impaired fracture healing in mouse models of Trisomy21 (Down syndrome). Bone. 2022 Sep;162:116471. Epub 2022 Jun 15 PubMed.
19. Peiris H, Duffield MD, Fadista J, Jessup CF, Kashmir V, Genders AJ, McGee SL, Martin AM, Saiedi M, Morton N, Carter R, Cousin MA, Kokotos AC, Oskolkov N, Volkov P, Hough TA, Fisher EM, Tybulewicz VL, Busciglio J, Coskun PE, Becker A, Belichenko PV, Mobley WC, Ryan MT, Chan JY, Laybutt DR, Coates PT, Yang S, Ling C, Groop L, Pritchard MA, Keating DJ. A Syntenic Cross Species Aneuploidy Genetic Screen Links RCAN1 Expression to β-Cell Mitochondrial Dysfunction in Type 2 Diabetes. PLoS Genet. 2016 May;12(5):e1006033. Epub 2016 May 19 PubMed.
20. Dard R, Tutunaru A, Bouassida M, Balde Camara A, Parizot E, Kassis N, Fortemps J, Cierniewski C, Racine C, Clemente ND, Vialard F, Janel N. Spermatogonial depletion and a spermatogenesis defect in the Dp(16)1Yey mouse model of Down syndrome. Reproduction. 2023 Dec 1; Epub 2023 Dec 1 PubMed.

Other Citations

1. Eugene Yu

External Citations

1. Strain 013530

Further Reading

No Available Further Reading