Coat Color-Facilitated Efficient Generation and Analysis of a Mouse Model of Down Syndrome Triplicated for All Human Chromosome 21 Orthologous Regions.

Yichen Li,Y Eugene Yu,Annie Pao,Tao Yu,Marcel Daadi,Zhuo Xing

doi:10.3390/genes12081215

Abstract

Down syndrome (DS) is one of the most complex genetic disorders in humans and a leading genetic cause of developmental delays and intellectual disabilities. The mouse remains an essential model organism in DS research because human chromosome 21 (Hsa21) is orthologously conserved with three regions in the mouse genome. Recent studies have revealed complex interactions among different triplicated genomic regions and Hsa21 gene orthologs that underlie major DS phenotypes. Because we do not know conclusively which triplicated genes are indispensable in such interactions for a specific phenotype, it is desirable that all evolutionarily conserved Hsa21 gene orthologs are triplicated in a complete model. For this reason, the Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+ mouse is the most complete model of DS to reflect gene dosage effects because it is the only mutant triplicated for all Hsa21 orthologous regions. Recently, several groups have expressed concerns that efforts needed to generate the triple compound model would be so overwhelming that it may be impractical to take advantage of its unique strength. To alleviate these concerns, we developed a strategy to drastically improve the efficiency of generating the triple compound model with the aid of a targeted coat color, and the results confirmed that the mutant mice generated via this approach exhibited cognitive deficits.

Highlights

Human trisomy 21, which is associated with Down syndrome (DS), occurs in one in approximately 800 live births [1]
Efficient Generation of Dp(10)1Yey;Dp(16)1Yey;Dp(17)1Yey Mice Facilitated by Coat Colors
Mouse tyrosinase minigene (Ty) driven by its own regulatory element was a coat color marker gene in the targeting vectors used in engineering of the three Dp mutants, namely, Dp(10)1Yey, Dp(16)1Yey, and Dp(17)1Yey [16,20]

Summary

Introduction

Human trisomy 21, which is associated with Down syndrome (DS), occurs in one in approximately 800 live births [1]. Considered by some investigators as a contiguous gene syndrome [4], the earliest group of genomic mouse models for DS included mouse trisomy 16, Ts65Dn, and Ts1Cje [5,6,7,8]. The mouse trisomy 16 model was developed based on the orthologous conservation between a part of human chromosome 21 (Hsa21) and the distal portion of mouse chromosome 16 (Mmu). There are some major deficiencies cation between Mmu and Mmu17 This extra chromosome spans the genomic region between Mrpl and the telomere on Mmu, which is orthologous to a region on Hsa and contains approximately 100 Hsa gene orthologs. Tc1, a transchromosomal mouse strain, represented an important model following associated with the mouse trisomy 16 model; namely, approximately 76.5% of Mmu the first group, and these mice carry a Hsa21-based transchromosome [12].

Methods

Results

Conclusion