Species: Mouse
Modification: Knock-In
Disease Relevance: Down's Syndrome, Alzheimer's Disease
Strain Name: B6.129P2-Dp(16Lipi-Zbtb21)1TybEmcf/J
Genetic Background: C57BL/6J
Availability: Available from the Jackson Lab: Strain 037183 and the European Mutant Mouse Archive EM:10557.

Summary

The Dp1Tyb 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). At weaning, 31 percent of female pups and 38 percent of male pups carry the Dp1Tyb segmental duplication (Dp1Tyb x C57BL/6J breeding scheme) (Lana-Elola et al., 2016). During gestation, Dp1Tyb embryos are present at the expected 50 percent ratio. The mutation, which transmits through both the male and female germline, results in perinatal lethality between birth and weaning (around 21 days).

To generate Dp1Tyb mice for experiments, it is recommended to use mice where the mutation has been inherited from the father to avoid confounding effects of the Dp1Tyb mutation in the mother during pregnancy. Moreover, the sub-Mendelian transmission rate at weaning needs to be taken into consideration.

Neuropathology

Despite the presence of three copies of mouse App, no amyloid-β plaque deposition is observed in Dp1Tyb hippocampus at 12-months of age (Lana-Elola et al., 2021). The model exhibits neurodevelopmental differences at 14 weeks of age, including reduced medial prefrontal cortex and dorsal hippocampus volumes, a reduced density of neurons, and an increased density of microglia in the hippocampus (Serrano et al., 2023). At 14 weeks of age, brain size is smaller and rounder compared to wild-type littermates, with regional volumetric changes. In addition, imbalances in hippocampal metabolites including glutamine and the glutamine/glutamate ratio are observed (Serrano et al., 2023).

Also of note, Dp1Tyb mice at 11 weeks of age show a decrease in neurons that bind isolectin-B4 (IB4), a marker of a subpopulation of non-peptidergic primary afferent neurons in dorsal root ganglia (Watson-Scales et al., 2018).

Behavioral/Neurological Phenotypes

Dp1Tyb mice have deficits in short-term associative recognition memory. At 17 weeks of age, they performed poorly in the short-term (10 minutes), but not the long-term (3 hours), object location discrimination test (Lana-Elola et al., 2021).

Dp1Tyb mice also exhibit reduced exploration and running-wheel activity, and slower movement at 12-15 weeks of age. This is not due to elevated anxiety levels, as in the elevated zero maze there was no difference in the performance of Dp1Tyb mice at 10 weeks of age (Lana-Elola et al., 2021). Dp1Tyb mice at 3 months of age also show prolonged decision-making in a T-maze paradigm, and altered theta dynamics (reduced frequency, increased hippocampal – medial prefrontal cortex coherence, increased modulation of hippocampal high gamma) (Chang et al., 2020). They do not exhibit an altered response in contextual or cued fear conditioning at 10 weeks of age (Lana-Elola et al., 2021).

Moreover, Dp1Tyb mice show impaired performance in the Rotarod test of motor coordination at 12 weeks of age, make more errors in the Locotronic test at 11 weeks of age, but have normal grip strength at 9 and 15 weeks of age (Lana-Elola et al., 2021; Watson-Scales et al., 2018)

Total sleep time is reduced in Dp1Tyb mice at 16 weeks of age and the mice exhibit a disrupted sleep pattern (Lana-Elola et al., 2021).

Other Phenotypes

The chromosomal duplication of Dp1Tyb mice also results in multiple non-neurological phenotypes. For example, at 12 weeks of age, Dp1Tyb animals have a slower heart rate, increased stroke volume, increased cardiac output, increased end-diastolic and end-systolic diameters, and increased left ventricular internal diameter at diastole and systole (Lana-Elola et al., 2021). In addition, Dp1Tyb embryos at day 14.5 of gestation have congenital heart defects including atrio-ventricular septal defects and ventricular septal defects (Lana-Elola et al., 2024; Lana-Elola et al., 2016). Moreover, Dp1Tyb mice at 13 weeks of age have impaired lung function, including increased minute and tidal volumes compared to wild-type littermates, under both normoxic and hypoxic conditions (Lana-Elola et al., 2021).

Dp1Tyb mice also suffer from hematologic abnormalities. At 16 weeks of age, they have macrocytic anemia. At 9-12 weeks of age, their bone marrow has normal numbers of erythroid progenitors and immature and mature megakaryocytes, but reduced percentages of B-lineage subsets. Also, at 9-12 weeks of age, the mutant mice exhibit splenomegaly, an increased number of splenocytes and enlarged spleens with increased splenic pro-erythroblasts, EryA and EryB erythroid progenitors, and immature and mature megakaryocytes. Many splenic lymphoid subsets are altered, including increased numbers of marginal zone B cells, germinal center B cells, plasma cells, and multiple subsets of CD4+ T cells, including naïve, effector, regulatory, and follicular helper T cells (Lana-Elola et al., 2021). Moreover, Dp1Tyb embryos in mothers who are iron deficient have severe subcutaneous edema and abnormal lymphatics at embryonic day 15.5 (Kalisch-Smith et al., 2021).

Skeletal abnormalities have also been reported. Dp1Tyb mice at 14 and 16 weeks of age exhibit deficits in bone mineral density and trabecular architecture (Thomas et al., 2020; Lana-Elola et al., 2021) ,and have overall bone deficits similar to those of humans with Down syndrome (Sloan et al., 2023). For example, the mutant mice have aberrant mineralization of the skull which is dependent on three copies of Dyrk1a (Redhead et al., 2023). Dp1Tyb mice also have cranial dysmorphologies including smaller size and brachycephaly (front-back shortening) at 16 weeks of age (Toussaint et al., 2021), as well as failure of secondary palate fusion and occasional holoprosencephaly (Kalisch-Smith et al., 2021). The earliest and most severe deficits in Dp1Tyb skulls are in bones of neural crest origin, which are seen at embryonic days 16.5 and 18.5 (Redhead et al., 2023).

Moreover, Dp1Tyb mice have otitis media reported at 17 weeks of age. Compared to wild-type littermates, Dp1Tyb mice also have substantially higher minimum sound intensity thresholds required to elicit a brainstem response when challenged with sounds at 8 kHz and 16 kHz and with clicks consisting of mixed frequencies at 14 weeks of age, indicating impaired hearing (Lana-Elola et al., 2021).

Metabolic abnormalities have also been reported in Dp1Tyb mice. At 17 weeks of age, they have various metabolite alterations both in fasted and non-fasted states. Of note, the levels of many types of saturated and unsaturated lysophosphatidylcholine and phosphatidyl choline lipids are reduced, while many triglycerides are increased. This profile may be associated with a pre-diabetic state (Lana-Elola et al., 2021)

Modification details

LoxP sites were inserted proximal to the lipase, member I (Lipi) gene and distal to the zinc finger and BTB domain containing 21 (Zbtb21) gene on mouse chromosome 16 in HM-1 embryonic stems cells. The region spanned by the lox sites was 23Mb long, including 145 coding genes, 114 which are orthologous to genes in human chromosome 21. Cre recombinase was transiently expressed in double-targeted embryonic stem cells to induce recombination between the loxP sites. Segmental duplication was confirmed by Southern blot analysis. Targeted clones were then injected into blastocysts to generate chimeric mice and these were bred to establish the C57BL/6J.129P2-Dp(16Lipi-Zbtb21)1TybEmcf/Nimr (Dp1Tyb) mouse strain by standard methods.

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.

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.

Dp(16)1Yey/+. This mouse model has an extra copy of approximately 65 percent of the mouse genes on chromosome 16 that are orthologous to Hsa21 generated by Cre/lox engineering. It is characterized by neuronal loss in the entorhinal cortex, locus coeruleus, and the basal forebrain magnocellular complex; increased tau pathology and increased astrocyte and microglia levels. Impairments in contextual memory, spatial learning, novel object recognition memory, and vocalizations. Altered motor coordination, sleep patterns, hearing, and vocalizations. Also, cardiopulmonary, craniofacial, skeletal, reproductive, immunological, and metabolic anomalies.

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 experts Elizabeth Fisher and Victor Tybulewicz

What would you say are the unique advantages of this model?
The Dp1Tyb exhibits multiple pathologies related to DS, effectively recapitulating the complex co-morbidity which occurs in individuals who have DS.

What do you think this model is best used for?
It is best used to study congenital heart defects, otitis media, craniofacial abnormalities, locomotor defects, sleep disturbances, bone anomalies, dysregulation of erythropoiesis and megakaryopoiesis, and non-amyloid-β-plaque dependent cognitive changes.

What caveats are associated with this model?
The absence of amyloid-β plaque pathology is a caveat.

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References

Research Models Citations

1. Ts65Dn
2. Dp9Tyb
3. Dp(16)1Yey/+
4. TcMAC21

Paper Citations

1. Lana-Elola E, Watson-Scales S, Slender A, Gibbins D, Martineau A, Douglas C, Mohun T, Fisher EM, Tybulewicz VL. Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel. Elife. 2016 Jan 14;5 PubMed. Correction.
2. Lana-Elola E, Cater H, Watson-Scales S, Greenaway S, Müller-Winkler J, Gibbins D, Nemes M, Slender A, Hough T, Keskivali-Bond P, Scudamore CL, Herbert E, Banks GT, Mobbs H, Canonica T, Tosh J, Noy S, Llorian M, Nolan PM, Griffin JL, Good M, Simon M, Mallon AM, Wells S, Fisher EM, Tybulewicz VL. Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of Down syndrome-related phenotypes. Dis Model Mech. 2021 Oct 1;14(10) Epub 2021 Oct 15 PubMed.
3. Serrano ME, Kim E, Siow B, Ma D, Rojo L, Simmons C, Hayward D, Gibbins D, Singh N, Strydom A, Fisher EM, Tybulewicz VL, Cash D. Investigating brain alterations in the Dp1Tyb mouse model of Down syndrome. Neurobiol Dis. 2023 Nov;188:106336. PubMed.
4. Watson-Scales S, Kalmar B, Lana-Elola E, Gibbins D, La Russa F, Wiseman F, Williamson M, Saccon R, Slender A, Olerinyova A, Mahmood R, Nye E, Cater H, Wells S, Yu YE, Bennett DL, Greensmith L, Fisher EM, Tybulewicz VL. Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration. PLoS Genet. 2018 May;14(5):e1007383. Epub 2018 May 10 PubMed.
5. Chang P, Bush D, Schorge S, Good M, Canonica T, Shing N, Noy S, Wiseman FK, Burgess N, Tybulewicz VL, Walker MC, Fisher EM. Altered Hippocampal-Prefrontal Neural Dynamics in Mouse Models of Down Syndrome. Cell Rep. 2020 Jan 28;30(4):1152-1163.e4. PubMed.
6. Lana-Elola E, Aoidi R, Llorian M, Gibbins D, Buechsenschuetz C, Bussi C, Flynn H, Gilmore T, Watson-Scales S, Haugsten Hansen M, Hayward D, Song OR, Brault V, Herault Y, Deau E, Meijer L, Snijders AP, Gutierrez MG, Fisher EM, Tybulewicz VL. Increased dosage of DYRK1A leads to congenital heart defects in a mouse model of Down syndrome. Sci Transl Med. 2024 Jan 24;16(731):eadd6883. Epub 2024 Jan 24 PubMed.
7. Kalisch-Smith JI, Ved N, Szumska D, Munro J, Troup M, Harris SE, Rodriguez-Caro H, Jacquemot A, Miller JJ, Stuart EM, Wolna M, Hardman E, Prin F, Lana-Elola E, Aoidi R, Fisher EM, Tybulewicz VL, Mohun TJ, Lakhal-Littleton S, De Val S, Giannoulatou E, Sparrow DB. Maternal iron deficiency perturbs embryonic cardiovascular development in mice. Nat Commun. 2021 Jun 8;12(1):3447. PubMed.
8. Thomas JR, LaCombe J, Long R, Lana-Elola E, Watson-Scales S, Wallace JM, Fisher EM, Tybulewicz VL, Roper RJ. Interaction of sexual dimorphism and gene dosage imbalance in skeletal deficits associated with Down syndrome. Bone. 2020 Jul;136:115367. Epub 2020 Apr 17 PubMed.
9. Sloan K, Thomas J, Blackwell M, Voisard D, Lana-Elola E, Watson-Scales S, Roper DL, Wallace JM, Fisher EM, Tybulewicz VL, Roper RJ. Genetic dissection of triplicated chromosome 21 orthologs yields varying skeletal traits in Down syndrome model mice. Dis Model Mech. 2023 Apr 1;16(4) Epub 2023 Apr 26 PubMed.
10. Redhead Y, Gibbins D, Lana-Elola E, Watson-Scales S, Dobson L, Krause M, Liu KJ, Fisher EM, Green JB, Tybulewicz VL. Craniofacial dysmorphology in Down syndrome is caused by increased dosage of Dyrk1a and at least three other genes. Development. 2023 Apr 15;150(8) Epub 2023 Apr 26 PubMed.
11. Toussaint N, Redhead Y, Vidal-García M, Lo Vercio L, Liu W, Fisher EM, Hallgrímsson B, Tybulewicz VL, Schnabel JA, Green JB. A landmark-free morphometrics pipeline for high-resolution phenotyping: application to a mouse model of Down syndrome. Development. 2021 Mar 12;148(18) PubMed.

Other Citations

1. Elizabeth Fisher

External Citations

1. Jackson Lab: Strain 037183
2. European Mutant Mouse Archive EM:10557

Further Reading