C57BL/6-Tg(DYRK1A)36Wjs/J

Stock number: 019460
Research areas: Cell Biology Research, Internal/Organ Research, Neurobiology Research

Description

These DYRK1A transgenic mice represent a clinically relevant animal model for a variety of Down Syndrome features including mental retardation, Alzheimer's Disease-like brain pathology, and increased food intake.

Detailed description

The DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1a) gene is located in the "Down Syndrome critical region" of human chromosome 21. It is ubiquitously expressed in both fetal and adult tissues of humans and rodents, with strongest expression in the heart and brain. Expression of DYRK1A protein is increased in the brains of human patients with Down Syndrome and Alzheimer's Disease. Interacting with a number of biological pathways, the full function of this gene is still being elucidated.

These hemizygous mice carry a single copy of a bacterial artificial chromosome (BAC) clone that contains the complete human DYRK1A genomic fragment, including the endogenous promoter. No other genes are included in the BAC. Protein expression is elevated 1.5-2 fold.

Hemizygotes show a significant impairment in hippocampal-dependent memory tasks as well as alterations in two forms of synaptic plasticity. Proliferation of embryonic neuronal cells is inhibited.

Many Down Syndrome patients show an early onset of Alzheimer's Disease and these mice demonstrate that DYRK1A hyperphosphorylates Tau at residues Ser-202, Thr-212, and Ser-404. DYRK1A also phosphorylates APP (amyloid beta (A4) precursor protein), RCAN1 (regulator of calcineurin 1), and PSEN1 (presenilin 1).

Transgenic mice exhibit significantly reduced bone mass despite decreased osteoclastogenesis. This is reminiscent of the osteoporotic bone phenotype in Down Syndrome patients.

Pathways that regulate food intake are also affected by DYRK1A. These transgenic animals demonstrate increase food intake through the Sir2-FOXO-sNPF/NPY pathway.

These transgenic mice represent a clinically relevant animal model for a variety of Down Syndrome features including mental retardation, Alzheimer's Disease-like brain pathology, and increased food intake. Hemizygotes show normal viability and fertility.

Development

A linearized BAC (clone 777J19 from the RPCI-11 library) encoding only full-length human DYRK1A (including the promoter) was injected into C57BL/6NCrjBgi embryos. A single copy was integrated in the mouse genome. This strain was backcrossed to C57BL/6J by the donating laboratory.

Allele

Symbol: Tg(DYRK1A)36Wjs
Name: transgene insertion 36, Woo-Joo Song
MGI accession ID: MGI:4867514
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Marker symbol: Tg(DYRK1A)36Wjs
Marker name: transgene insertion 36, Woo-Joo Song
Chromosome: UN
Strain of origin: C57BL/6NCrjBgi
Expressed genes: DYRK1A,dual specificity tyrosine phosphorylation regulated kinase 1A,human
Molecular note: This transgene consists of a bacterial artificial chromosome clone containing the complete human DYRK1A genomic DNA fragment, including the endogenous promoter (777J19 BAC clone from the RPCI-11 human BAC library). FISH and quantitative PCR analysis shows a single chromosomal integration of the DNA and about a 1.5-fold overexpression of total Dyrk1a (both mouse and human) protein. Two lines 36 and 46 were created, with line 36 entered as the representative line.