Mouse-based genetic modeling and analysis of Down syndrome

Abstract

Introduction: Down syndrome (DS), caused by human trisomy 21 (Ts21), can be considered as a prototypical model for understanding the effects of chromosomal aneuploidies in other diseases. Human chromosome 21 (Hsa21) is syntenically conserved with three regions in the mouse genome.

Sources of data: A review of recent advances in genetic modeling and analysis of DS. Using Cre/loxP-mediated chromosome engineering, a substantial number of new mouse models of DS have recently been generated, which facilitates better understanding of disease mechanisms in DS.

Areas of agreement: Based on evolutionary conservation, Ts21 can be modeled by engineered triplication of Hsa21 syntenic regions in mice. The validity of the models is supported by the exhibition of DS-related phenotypes.

Areas of controversy: Although substantial progress has been made, it remains a challenge to unravel the relative importance of specific candidate genes and molecular mechanisms underlying the various clinical phenotypes.

Growing points: Further understanding of mechanisms based on data from mouse models, in parallel with human studies, may lead to novel therapies for clinical manifestations of Ts21 and insights to the roles of aneuploidies in other developmental disorders and cancers.

Keywords: Down syndrome; chromosome engineering; human trisomy 21; mouse models.

Fig. 1

Shared syntenies between Hsa21 and three regions in the mouse genome which are located on Mmu10, Mmu16 and Mmu17. The endpoints of the syntenic regions in mice are indicated.

Fig. 2

The strategy to generate deletions and duplications in mouse ES cells using Cre/loxP-mediated chromosome engineering. To generate Dp and Df, loxP is inserted into two endpoints of an orthologous region of Hsa21 in the genome of mouse ES cells with two different positive selection markers, such as the neomycin and puromycin resistance genes. A Cre expression vector is then electroporated into the double-targeted cells to induce recombination. (A) If two loxP sites are located in cis and orientated in the same direction in relationship to the centromere, the recombination will result in a Df. (B) If two loxP sites are located in trans and orientated in the same direction in relationship to the centromere, the recombination will result in a Dp and a Df. The genotypes of engineered ES cells are confirmed by Southern blot analysis and fluorescence in situ hybridization. Afterwards, these cells are used to generate chimeras by injecting them into blastocysts. Germline transmission will lead to establishment of mouse mutants carrying a desired Dp or Df. Arrow head, loxP.

Fig. 3

Mouse mutants which carry a triplication of a Hsa21 syntenic region. A solid line represents the region triplicated for a Hsa21 syntenic region in a mouse model listed in the table.

Fig. 4

Mouse mutants which carry a deletion of a Hsa21 syntenic region. An open line represents the region deleted for a Hsa21 syntenic region in a mouse model listed in the table.