Mouse models for Down syndrome-associated developmental cognitive disabilities

Abstract

Down syndrome (DS) is mainly caused by the presence of an extra copy of human chromosome 21 (Hsa21) and is a leading genetic cause for developmental cognitive disabilities in humans. The mouse is a premier model organism for DS because the regions on Hsa21 are syntenically conserved with three regions in the mouse genome, which are located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. With the advance of chromosomal manipulation technologies, new mouse mutants have been generated to mimic DS at both the genotypic and phenotypic levels. Further mouse-based molecular genetic studies in the future may lead to the unraveling of the mechanisms underlying DS-associated developmental cognitive disabilities, which would lay the groundwork for developing effective treatments for this phenotypic manifestation. In this review, we will discuss recent progress and future challenges in modeling DS-associated developmental cognitive disability in mice with an emphasis on hippocampus-related phenotypes.

Fig. 1

Hsa21 and the mouse syntenic regions. There are 3 regions in the mouse genome that are syntenically conserved with Hsa21. The endpoints of these syntenic regions are shown. All the Hsa21 orthologs of the mouse genes in the 3 syntenic regions are located on human 21q.

Fig. 2

Hsa21, the mouse syntenic regions and the segmentally trisomic mouse models. The endpoints of the syntenic regions and the segmental trisomies in the mouse models are shown.

Fig. 3

Schematic representation of a breeding strategy to generate a mouse model of DS trisomic for all Hsa21 syntenic regions by crossing mouse mutants carrying individual duplications.

Fig. 4

A strategy to generate a constitutional transchromosomic mouse model [Kazuki et al., 2003]. A loxP is inserted into the telomere region of a mouse autosome in mouse ES cells while another loxP is inserted into the centromere region of human 21q. The human chromosome can be delivered to the mouse ES cells using microcell-mediated chromosome transfer. Cre/loxP-mediated chromosomal rearrangement in the ES cells can lead to transferring of human 21q to the targeted autosome. The resultant ES cells can be used to generate germ line chimeras by injecting them into wild-type mouse blastocysts.