Mouse models of Down syndrome

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Mouse models have frequently been used to study Down syndrome due to the close similarity in the genomes of mice and humans, and the prevalence of mice usage in laboratory research.

Contents

Background

Trisomy 21, an extra copy of the 21st chromosome, is responsible for causing Down syndrome, and the mouse chromosome 16 closely resembles human chromosome 21. [1] In 1979, trisomy of the mouse chromosome 16 (Ts16) initially showed potential to be a model organism for human Down syndrome. [2] However, Ts16 embryos rarely survive until birth, making them unable to serve as a model for behavior and postnatal development. [3] 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 imbalances. Because of this disadvantage, more specific mouse models have been utilized.

Ts65Dn

Model

The Ts65Dn mouse model was first introduced in 1993, [4] 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 phenotypes are produced, including behavioral abnormalities and cognitive defects. [5]

DNA damage

Ts65Dn mouse muscle stem cells accumulate DNA damage. [6] These cells also over-express a histone deubiquitinating enzyme, Usp16, which regulates the DNA damage response. [6] These dysfunctions of muscle stem cells may impair muscle regeneration and contribute to Down syndrome pathologies.

T65Dn mice have significantly reduced numbers of hematopoietic stem cells (HSCs) along with an increase in HSC production of reactive oxygen species compared to euploid cells of wild-type littermates. [7] 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. [8] 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 may selectively impair the ability of HSCs to repair double-strand breaks, and this impairment may contribute to Down syndrome associated hematological abnormalities and malignancies. [8]

Findings

This model was studied to understand the neurological basis of its mental impairment. It was found that it exhibited inhibition in the dentate gyrus, and that GABAA antagonists were able to resolve some of this impairment. [9] 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. [10] They also contained abnormally large neural synapses and other structural changes. [11]

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.

Findings

  1. Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome.
  2. Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome.
  3. 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 Francisco 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. [12]

Findings

  1. Both female and male Ts1Cje mice are fertile.
  2. Unlike Ts65Dn mice, Ts1Cje mice show more deficits in spatial than non-spatial learning.
  3. Ts1Cje mice do not display the age related decline in BFCN neurons typical of Ts65Dn mice. [12]
  4. Expression of Jak-STAT signalling pathway genes has been characterized throughout development in Ts1Cje mice. [13]

Related Research Articles

Genomic imprinting is an epigenetic phenomenon that causes genes to be expressed or not, depending on whether they are inherited from the female or male parent. Genes can also be partially imprinted. Partial imprinting occurs when alleles from both parents are differently expressed rather than complete expression and complete suppression of one parent's allele. Forms of genomic imprinting have been demonstrated in fungi, plants and animals. In 2014, there were about 150 imprinted genes known in mice and about half that in humans. As of 2019, 260 imprinted genes have been reported in mice and 228 in humans.

<span class="mw-page-title-main">Meiosis</span> Cell division producing haploid gametes

Meiosis is a special type of cell division of germ cells and apicomplexans in sexually-reproducing organisms that produces the gametes, the sperm or egg cells. It involves two rounds of division that ultimately result in four cells, each with only one copy of each chromosome (haploid). Additionally, prior to the division, genetic material from the paternal and maternal copies of each chromosome is crossed over, creating new combinations of code on each chromosome. Later on, during fertilisation, the haploid cells produced by meiosis from a male and a female will fuse to create a zygote, a cell with two copies of each chromosome again.

<span class="mw-page-title-main">Aneuploidy</span> Presence of an abnormal number of chromosomes in a cell

Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes. A cell with any number of complete chromosome sets is called a euploid cell.

<span class="mw-page-title-main">Prenatal testing</span> Testing for diseases or conditions in a fetus

Prenatal testing is a tool that can be used to detect some birth defects at various stages prior to birth. Prenatal testing consists of prenatal screening and prenatal diagnosis, which are aspects of prenatal care that focus on detecting problems with the pregnancy as early as possible. These may be anatomic and physiologic problems with the health of the zygote, embryo, or fetus, either before gestation even starts or as early in gestation as practicable. Screening can detect problems such as neural tube defects, chromosome abnormalities, and gene mutations that would lead to genetic disorders and birth defects, such as spina bifida, cleft palate, Down syndrome, trisomy 18, Tay–Sachs disease, sickle cell anemia, thalassemia, cystic fibrosis, muscular dystrophy, and fragile X syndrome. Some tests are designed to discover problems which primarily affect the health of the mother, such as PAPP-A to detect pre-eclampsia or glucose tolerance tests to diagnose gestational diabetes. Screening can also detect anatomical defects such as hydrocephalus, anencephaly, heart defects, and amniotic band syndrome.

<span class="mw-page-title-main">Germline mutation</span> Inherited genetic variation

A germline mutation, or germinal mutation, is any detectable variation within germ cells. Mutations in these cells are the only mutations that can be passed on to offspring, when either a mutated sperm or oocyte come together to form a zygote. After this fertilization event occurs, germ cells divide rapidly to produce all of the cells in the body, causing this mutation to be present in every somatic and germline cell in the offspring; this is also known as a constitutional mutation. Germline mutation is distinct from somatic mutation.

<span class="mw-page-title-main">GATA1</span> Protein-coding gene in humans

GATA-binding factor 1 or GATA-1 is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded by the GATA1 and Gata1 genes, respectively. These genes are located on the X chromosome in both species.

<span class="mw-page-title-main">Down syndrome research</span>

Research of Down syndrome-related genes is based on studying the genes located on chromosome 21. In general, this leads to an overexpression of the genes. Understanding the genes involved may help to target medical treatment to individuals with Down syndrome. It is estimated that chromosome 21 contains 200 to 250 genes. Recent research has identified a region of the chromosome that contains the main genes responsible for the pathogenesis of Down syndrome, located proximal to 21q22.3. The search for major genes involved in Down syndrome characteristics is normally in the region 21q21–21q22.3.

<span class="mw-page-title-main">Ectrodactyly–ectodermal dysplasia–cleft syndrome</span> Medical condition

Ectrodactyly–ectodermal dysplasia–cleft syndrome, or EEC, and also referred to as EEC syndrome and split hand–split foot–ectodermal dysplasia–cleft syndrome is a rare form of ectodermal dysplasia, an autosomal dominant disorder inherited as a genetic trait. EEC is characterized by the triad of ectrodactyly, ectodermal dysplasia, and facial clefts. Other features noted in association with EEC include vesicoureteral reflux, recurrent urinary tract infections, obstruction of the nasolacrimal duct, decreased pigmentation of the hair and skin, missing or abnormal teeth, enamel hypoplasia, absent punctae in the lower eyelids, photophobia, occasional cognitive impairment and kidney anomalies, and conductive hearing loss.

A chromosomal abnormality, chromosomal anomaly, chromosomal aberration, chromosomal mutation, or chromosomal disorder is a missing, extra, or irregular portion of chromosomal DNA. These can occur in the form of numerical abnormalities, where there is an atypical number of chromosomes, or as structural abnormalities, where one or more individual chromosomes are altered. Chromosome mutation was formerly used in a strict sense to mean a change in a chromosomal segment, involving more than one gene. Chromosome anomalies usually occur when there is an error in cell division following meiosis or mitosis. Chromosome abnormalities may be detected or confirmed by comparing an individual's karyotype, or full set of chromosomes, to a typical karyotype for the species via genetic testing.

The immortal DNA strand hypothesis was proposed in 1975 by John Cairns as a mechanism for adult stem cells to minimize mutations in their genomes. This hypothesis proposes that instead of segregating their DNA during mitosis in a random manner, adult stem cells divide their DNA asymmetrically, and retain a distinct template set of DNA strands in each division. By retaining the same set of template DNA strands, adult stem cells would pass mutations arising from errors in DNA replication on to non-stem cell daughters that soon terminally differentiate. Passing on these replication errors would allow adult stem cells to reduce their rate of accumulation of mutations that could lead to serious genetic disorders such as cancer.

<span class="mw-page-title-main">Cat eye syndrome</span> Genetic partial duplication of chromosome 22

Cat-eye syndrome (CES) or Schmid–Fraccaro syndrome is a rare condition caused by an abnormal extra chromosome, i.e. a small supernumerary marker chromosome. This chromosome consists of the entire short arm and a small section of the long arm of chromosome 22. In consequence, individuals with the cat-eye syndrome have three (trisomic) or four (tetrasomic) copies of the genetic material contained in the abnormal chromosome instead of the normal two copies. The prognosis for patients with CES varies depending on the severity of the condition and their associated signs and symptoms, especially when heart or kidney abnormalities are seen.

<span class="mw-page-title-main">HOXA9</span> Protein-coding gene in humans

Homeobox protein Hox-A9 is a protein that in humans is encoded by the HOXA9 gene.

<span class="mw-page-title-main">HOXD11</span> Protein-coding gene in humans

Homeobox protein Hox-D11 is a protein that in humans is encoded by the HOXD11 gene.

<span class="mw-page-title-main">LBH (gene)</span> Protein-coding gene in the species Homo sapiens

The LBH gene is a highly conserved human gene that produces the LBH protein, a transcription co-factor in the Wnt/β-catenin pathway. Upon transcriptional activation of β-catenin, LBH goes on to act as a regulator of cell proliferation and differentiation through multiple transcriptional targets. The gene is located on the p arm of chromosome 2 and is roughly 28 kb long. Current ongoing studies are examining its role in developmental and oncological settings.

<span class="mw-page-title-main">DOP1B</span> Protein-coding gene in the species Homo sapiens

DOP1B is a human gene located just above the Down Syndrome chromosomal region (DSCR) located at 21p22.2 sub-band. Although the exact function of this gene is not yet fully understood, it has been proven to play a role in multiple biological processes, and its over-expression (triplication) has been linked to multiple facets of the Down Syndrome phenotype, most notably mental retardation.

<span class="mw-page-title-main">Acute megakaryoblastic leukemia</span> Medical condition

Acute megakaryoblastic leukemia (AMKL) is life-threatening leukemia in which malignant megakaryoblasts proliferate abnormally and injure various tissues. Megakaryoblasts are the most immature precursor cells in a platelet-forming lineage; they mature to promegakaryocytes and, ultimately, megakaryocytes which cells shed membrane-enclosed particles, i.e. platelets, into the circulation. Platelets are critical for the normal clotting of blood. While malignant megakaryoblasts usually are the predominant proliferating and tissue-damaging cells, their similarly malignant descendants, promegakaryocytes and megakaryocytes, are variable contributors to the malignancy.

Potocki–Lupski syndrome (PTLS), also known as dup(17)p11.2p11.2 syndrome, trisomy 17p11.2 or duplication 17p11.2 syndrome, is a contiguous gene syndrome involving the microduplication of band 11.2 on the short arm of human chromosome 17 (17p11.2). The duplication was first described as a case study in 1996. In 2000, the first study of the disease was released, and in 2007, enough patients had been gathered to complete a comprehensive study and give it a detailed clinical description. PTLS is named for two researchers involved in the latter phases, Drs. Lorraine Potocki and James R. Lupski of Baylor College of Medicine.

Elizabeth Mary Claire Fisher is a British geneticist and Professor at University College London. Her research investigates the degeneration of motor neurons during amyotrophic lateral sclerosis and Alzheimer's disease triggered by Down syndrome.

Transient myeloproliferative disease (TMD) occurs in a significant percentage of individuals born with the congenital genetic disorder, Down syndrome. It may occur in individuals who are not diagnosed with the syndrome but have some hematological cells containing genetic abnormalities that are similar to those found in Down syndrome. TMD usually develops in utero, is diagnosed prenatally or within ~3 months of birth, and thereafter resolves rapidly and spontaneously. However, during the prenatal-to-postnatal period, the disease may cause irreparable damage to various organs and in ~20% of individuals death. Moreover, ~10% of individuals diagnosed with TMD develop acute megakaryoblastic leukemia at some time during the 5 years following its resolution. TMD is a life-threatening, precancerous condition in fetuses as well as infants in their first few months of life.

X chromosome reactivation (XCR) is the process by which the inactive X chromosome (the Xi) is re-activated in the cells of eutherian female mammals. Therian female mammalian cells have two X chromosomes, while males have only one, requiring X-chromosome inactivation (XCI) for sex-chromosome dosage compensation. In eutherians, XCI is the random inactivation of one of the X chromosomes, silencing its expression. Much of the scientific knowledge currently known about XCR comes from research limited to mouse models or stem cells.

References

  1. ↑ Reeves RH, Irving NG, Moran TH, Wohn A, Kitt C, Sisodia SS, et al. (October 1995). "A mouse model for Down syndrome exhibits learning and behaviour deficits". Nature Genetics. 11 (2): 177–84. doi:10.1038/ng1095-177. PMID   7550346. S2CID   24966761.
  2. ↑ Patterson D, Costa AC (February 2005). "Down syndrome and genetics - a case of linked histories". Nature Reviews. Genetics. 6 (2): 137–47. doi:10.1038/nrg1525. PMID   15640809. S2CID   39792702.
  3. ↑ Rueda N, Flórez J, Martínez-Cué C (2012-05-22). "Mouse models of Down syndrome as a tool to unravel the causes of mental disabilities". Neural Plasticity. 2012: 584071. doi: 10.1155/2012/584071 . PMC   3364589 . PMID   22685678.
  4. ↑ T, Davisson, M; C, Schmidt; H, Reeves, R; G, Irving, N; C, Akeson, E; S, Harris, B; T, Bronson, R (1993-01-01). "Segmental trisomy as a mouse model for Down syndrome". Faculty Research 1990 - 1999. 384: 117–133. PMID   8115398.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ↑ Rueda N, Flórez J, Martínez-Cué C (2012-05-22). "Mouse models of Down syndrome as a tool to unravel the causes of mental disabilities". Neural Plasticity. 2012: 584071. doi: 10.1155/2012/584071 . PMC   3364589 . PMID   22685678.
  6. 1 2 Pawlikowski B, Betta ND, Elston T, Williams DA, Olwin BB (March 2018). "Muscle stem cell dysfunction impairs muscle regeneration in a mouse model of Down syndrome". Scientific Reports. 8 (1): 4309. Bibcode:2018NatSR...8.4309P. doi:10.1038/s41598-018-22342-5. PMC   5844921 . PMID   29523805.
  7. ↑ Lorenzo LP, Shatynski KE, Clark S, Yarowsky PJ, Williams MS (August 2013). "Defective thymic progenitor development and mature T-cell responses in a mouse model for Down syndrome". Immunology. 139 (4): 447–58. doi:10.1111/imm.12092. PMC   3719062 . PMID   23432468.
  8. 1 2 Wang Y, Chang J, Shao L, Feng W, Luo Y, Chow M, et al. (June 2016). "Hematopoietic Stem Cells from Ts65Dn Mice Are Deficient in the Repair of DNA Double-Strand Breaks". Radiation Research. 185 (6): 630–7. Bibcode:2016RadR..185..630W. doi:10.1667/RR14407.1. PMC   4943077 . PMID   27243896.
  9. ↑ Fernandez F, Morishita W, Zuniga E, Nguyen J, Blank M, Malenka RC, Garner CC (April 2007). "Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome". Nature Neuroscience. 10 (4): 411–3. doi:10.1038/nn1860. PMID   17322876. S2CID   29468421.
  10. ↑ Holtzman DM, Santucci D, Kilbridge J, Chua-Couzens J, Fontana DJ, Daniels SE, et al. (November 1996). "Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome". Proceedings of the National Academy of Sciences of the United States of America. 93 (23): 13333–8. Bibcode:1996PNAS...9313333H. doi: 10.1073/pnas.93.23.13333 . JSTOR   40794. PMC   24093 . PMID   8917591.
  11. ↑ Belichenko PV, Masliah E, Kleschevnikov AM, Villar AJ, Epstein CJ, Salehi A, Mobley WC (December 2004). "Synaptic structural abnormalities in the Ts65Dn mouse model of Down Syndrome". The Journal of Comparative Neurology. 480 (3): 281–98. doi:10.1002/cne.20337. PMID   15515178. S2CID   23205964.
  12. 1 2 Sago H, Carlson EJ, Smith DJ, Kilbridge J, Rubin EM, Mobley WC, et al. (May 1998). "Ts1Cje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities". Proceedings of the National Academy of Sciences of the United States of America. 95 (11): 6256–61. Bibcode:1998PNAS...95.6256S. doi: 10.1073/pnas.95.11.6256 . PMC   27649 . PMID   9600952.
  13. ↑ Lee HC, Md Yusof HH, Leong MP, Zainal Abidin S, Seth EA, Hewitt CA, et al. (September 2019). "Gene and protein expression profiles of JAK-STAT signalling pathway in the developing brain of the Ts1Cje down syndrome mouse model". The International Journal of Neuroscience. 129 (9): 871–881. doi:10.1080/00207454.2019.1580280. PMID   30775947. S2CID   73478915.
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