Mouse models have frequently been used to study
Down syndrome
Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual dis ...
due to the close similarity in the
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
s of mice and humans, and the prevalence of mice usage in laboratory research.
Background
Trisomy
A trisomy is a type of polysomy in which there are three instances of a particular chromosome, instead of the normal two. A trisomy is a type of aneuploidy (an abnormal number of chromosomes).
Description and causes
Most organisms that reprodu ...
21, an extra copy of the
21st chromosome, is responsible for causing Down syndrome, and the mouse
chromosome
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
16 closely resembles human chromosome 21. In 1979, trisomy of the mouse chromosome 16 (Ts16) initially showed potential to be a model organism for human Down syndrome. However, Ts16 embryos rarely survive until birth, making them unable to serve as a model for behavior and postnatal development. This dissimilarity in survival between species arises from the presence of genes on mouse chromosome 16 that are not present on human chromosome 21, introducing additional
gene dosage Gene dosage is the number of copies of a particular gene present in a genome. Gene dosage is related to the amount of gene product (proteins or functional RNAs) the cell is able to express. Since, a gene acts as a template, the number of templates ...
imbalances. Because of this disadvantage, more specific mouse models have been utilized.
Ts65Dn
Model
The Ts65Dn mouse model was first introduced in 1993, and more specifically resembles human trisomy 21 than the Ts16 model. In Ts65Dn, cells possess an extra copy of a segment of genes on chromosome 16 as well as a segment of genes on chromosome 17. From this model, various Down syndrome
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
s are produced, including
behavioral abnormalities and
cognitive
Cognition refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...
defects.
DNA damage
Ts65Dn mouse muscle
stem cell
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
s accumulate
DNA damage
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
.
These cells also over-express a
histone
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wr ...
deubiquitinating enzyme
Deubiquitinating enzymes (DUBs), also known as deubiquitinating peptidases, deubiquitinating isopeptidases, deubiquitinases, ubiquitin proteases, ubiquitin hydrolases, ubiquitin isopeptidases, are a large group of proteases that cleave ubiquitin f ...
,
Usp16
Ubiquitin carboxyl-terminal hydrolase 16 is an enzyme that in humans is encoded by the ''USP16'' gene.
This gene encodes a deubiquitinating enzyme that is phosphorylated at the onset of mitosis and then dephosphorylated at the metaphase/anaphase ...
, which regulates the DNA damage response.
These dysfunctions of muscle stem cells may impair muscle regeneration and contribute to
Down syndrome
Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual dis ...
pathologies.
T65Dn mice have significantly reduced numbers of
hematopoietic stem cell
Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within t ...
s (HSCs) along with an increase in HSC production of
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
compared to euploid cells of wild-type littermates.
Spontaneous DNA double-strand breaks are significantly increased in HSCs from Ts65Dn mice, and this correlates with significantly reduced HSC clonogenic activity compared to controls.
HSCs from Ts65DN mice are also less proficient in
repair of DNA double-strand breaks than cells from wild type mice. These observations suggest that an additional copy of genes on
chromosome 21
Chromosome 21 is one of the 23 pairs of chromosomes in humans. Chromosome 21 is both the smallest human autosome and chromosome, with 48 million base pairs (the building material of DNA) representing about 1.5 percent of the total DNA in cells. ...
may selectively impair the ability of HSCs to repair double-strand breaks, and this impairment may contribute to
Down syndrome
Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual dis ...
associated hematological abnormalities and malignancies.
Findings
This model was studied to understand the neurological basis of its
mental impairment
Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation,Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signific ...
. It was found that it exhibited inhibition in the
dentate gyrus
The dentate gyrus (DG) is part of the hippocampal formation in the temporal lobe of the brain, which also includes the hippocampus and the subiculum. The dentate gyrus is part of the hippocampal trisynaptic circuit and is thought to contribute ...
, and that
GABAA antagonists were able to resolve some of this impairment. These mice were found to experience a delay in development, exhibit unusual behaviors similar to human retardation, and eventually encounter astrocytic hypertrophy and other forms of
neurodegeneration
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
. They also contained abnormally large neural synapses and other structural changes.
Dp(16)1Yu
Model
The Dp(16)1Yu model (also referred to as Dp(16)1Yey) contains a partial duplication of the mouse chromosome 16 (MMU16). Unlike the Ts65Dn model, Dp(16)1Yu contains a duplication of only the parts of chromosome 16 that are homologous to human chromosome 21. This makes the Dp(16)1Yu model a more genetically accurate representation of Down Syndrome. This model presents an array of symptoms, including an increased rate of heart defects and learning and memory deficits which are comparable to symptoms seen in Down Syndrome. These mice also show an increased rate of birth defects in the pancreas (see
annuler pancreas) and
intestinal malrotation
Intestinal malrotation is a congenital anomaly of rotation of the midgut. It occurs during the first trimester as the fetal gut undergoes a complex series of growth and development. Malrotation can lead to a dangerous complication called volvulus. ...
.
Findings
#
Pharmacotherapy
Pharmacotherapy is therapy using pharmaceutical drugs, as distinguished from therapy using surgery (surgical therapy), radiation (radiation therapy), movement ( physical therapy), or other modes. Among physicians, sometimes the term ''medical the ...
for cognitive impairment in a mouse model of Down syndrome.
# Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome.
#
Synaptic structural abnormalities in the Ts65Dn mouse model of down syndrome.
Ts1Cje
Model
The Ts1Cje mouse model of Down Syndrome was developed at the University of California San Franciscco in 1997. This model has a partial triplication of MMU 16 that is smaller than the triplicated region in the Ts65Dn model. Ts1Cje triplication contains what has been identified as the Down Syndrome Critical Region, a region involved in all forms of DS. Ts1Cje mice have three copies of the distal portion of MMU16 from the genes ''Sod1 to Mx1''. However, the Sod1 gene does not have three active copies.
Findings
# Both female and male Ts1Cje mice are fertile.
# Unlike Ts65Dn mice, Ts1Cje mice show more deficits in spatial than non-spatial learning.
# Ts1Cje mice do not display the age related decline in BFCN neurons typical of Ts65Dn mice.
# Expression of Jak-STAT signalling pathway genes has been characterized throughout development in Ts1Cje mice.
References
{{reflist
Down syndrome
Laboratory mice