Species: Mouse
Disease Relevance: Down's Syndrome, Alzheimer's Disease
Strain Name: C57BL/6J.129P2-Dp(16Lipi-Hunk)9TybEmcf/TybH
Genetic Background: C57BL/6J
Availability: Available from the European Mutant Mouse Archive (EMMA) (strain ID EM:10565).
 

Summary

Dp9Tyb was initially developed as a model for studying Down syndrome and therefore this mouse strain contains duplications of regions orthologous to human chromosome 21. It could possibly be a relevant model for Alzheimer’s disease (AD) since it carries an additional copy of the App gene, albeit the duplication may not include all genes relevant to Down syndrome-associated AD, such as Dyrk1a and Bace2 (Elizabeth Fisher and Victor Tybulewicz personal communication, Nov 2024).

Neuropathology

No neuropathological studies have been reported on Dp9Tyb mice.

Behavioral/Neurological Phenotypes

Dp9Tyb mice at 12 weeks of age have no locomotor defects in the Rotarod test (Watson-Scales et al., 2018).

Other Phenotypes

Unlike other DS mouse models, Dp9Tyb mice have no congenital heart defects at embryonic day 14.5 (Lana-Elola et al., 2016). Moreover, rather than having bone deficits commonly seen in other DS models, Dp9Tyb mice had improved trabecular and cortical bone measurements compared to control mice at 16-18 weeks of age (Sloan et al., 2023).

Modification details

Lana-Elola and colleagues used gene targeting to insert loxP sites proximal to the lipase gene Lipi and distal to the hormonally up-regulated Neu-associated kinase gene Hunk using MICERs MHPP352i17 (coordinates of homology region 16:74930370–16:74937378 Mb, mouse assembly GRCm38/mm10) and MHPP323h04 (16:90563769 – 16:90577148 Mb) respectively (Lana-Elola et al., 2016). C57BL/6J.129P2-Dp(16Lipi-Hunk)9TybEmcf/Nimr (Dp9Tyb) mice were generated using an in vivo Cre-mediated recombination strategy whereby female mice containing the Hprt^tm1(cre)Mnn allele and the two loxP sites located in trans configuration on mouse chromosome 16, were bred to C57BL/6JNimr males. Cre activity in the female germline from the Hprt^tm1(cre)Mnn allele resulted in pups (~1%) with recombination between the loxP sites generating the duplication (Lana-Elola et al., 2016).

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.

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

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References

Research Models Citations

1. Ts65Dn
2. Dp1Tyb
3. Dp(16)1Yey/+
4. TcMAC21

Paper Citations

1. 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.
2. 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.
3. 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.

Other Citations

1. Elizabeth Fisher

External Citations

1. strain ID EM:10565

Further Reading

No Available Further Reading