Because DS is caused by the triplication of Hsa21, and the orthologs of the Hsa21 genes are located in three syntenic regions in the mouse genome, an ideal mouse model of DS should harbor Hsa21 (13) or segmental trisomies for all three mouse syntenic regions. These types of models have been considered important genetic tools for advancing DS research (33
mice generated from this study carry a genotype of such desired models.
Recent studies suggest that the alteration of a biological pathway and, in turn, a DS phenotype could be the consequence of a functional interaction of two or more triplicated Hsa21 gene orthologs (39
, one of the gene orthologs triplicated in Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+
mice, has been proposed as a causative ortholog for the abnormal cognitively relevant phenotype in DS (39
). However, the triplication of the Dyrk1a
ortholog alone by BAC transgenics causes enhanced hippocampal LTP in mutant mice (41
), even though Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+
mice exhibited reduced hippocampal LTP. Similarly, the triplication of 12 genes in the Hsa21 syntenic region on Mmu17 was found to be associated with enhanced hippocampal LTP in Ts1Yah mice (25
). The latter suggests that the cognitively relevant phenotypes in DS are the consequence of interactions among Hsa21 genes whose orthologs are located in different syntenic regions in mice. Therefore, Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+
is a more desirable genotype for modeling human trisomy 21. Furthermore, our results show that when we recreated the evolutionarily conserved genotype, the final outcome at the phenotypic level also appears to be evolutionarily conserved: the DS-related abnormalities in the central nervous system, including impairments in learning, memory and hippocampal LTP as well as hydrocephalus (10
). These results strengthen the possibility that the Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+
mice could potentially be used as one of the reference models for understanding developmental cognitive disability in DS.
Another popular mouse model for DS is Ts65Dn mice. Ts65Dn is a derivative chromosome of a reciprocal translocation, and the studies on other mutant mice have shown that the presence of translocation chromosomes may be associated with impaired gametogenesis (42
). Ts65Dn mice are maintained in the B6C3HF1 background, and backcrossing Ts65Dn mice to inbred wild-type mice has led to drastic reduction in fertility, probably because the adverse effects of the Ts65Dn chromosome on spermatogenesis and oogenesis are more severe in an inbred background. On the other hand, no impairment of fertility has been observed after Dp(10)1Yey/+, Dp(16)1Yey/+ and Dp(17)1Yey/+ mice were backcrossed to C57BL/6J mice for five generations, probably because these mutants do not carry a translocation chromosome and the third copies of the Hsa21 syntenic regions in these mutants are present as genomic duplications embedded within the original chromosomes. Ts65Dn mice and Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+
mice shared the similarities in impairments in hippocampal-mediated behaviors and hippocampal LTP (19
), suggesting the critical genes associated with these phenotypes may reside within the Mrpl39
genomic segment (Fig. ). However, the result from Ts1Yah mice suggests that the orthologs of Hsa21 genes in other syntenic regions also contribute significantly to the DS-related phenotypes in patients with trisomy 21 and in Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+
Hydrocephalus and associated aqueductal stenosis has been observed in patients with DS (50
). On the basis of the analysis of 2894 cases of DS, Torfs and Christianson found a 10.1-fold increase in the incidence of hydrocephalus in DS patients compared with the non-DS population (P
). Among mouse models of DS, enlargement of brain ventricles has been observed in Ts2Cje mice (54
) that have the same triplicated region as the Ts65Dn mice (55
). However, the hydrocephalus observed in Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+
mice has not been reported in any other mouse models of DS. There are no known genes on Hsa21 at present that are associated with hydrocephalus. Our result suggests that hydrocephalus may be caused by the triplication of an Hsa21 gene ortholog that is not triplicated in Ts2Cje or by the functional interactions between triplicated genes located in the Mrpl39
region (Fig. ) and in another Hsa21 syntenic region(s). These possibilities can now be examined in animal models for the first time.
Beta-amyloid plaques and neurofibrillary tangles are the most commonly observed Alzheimer-type neuropathology in patients with DS after ~40 years of age. But the analysis of Ts65Dn mice and Tc1 mice revealed no amyloid plaques or neurofibrillary tangles in these models (13
). We also performed a preliminary examination of the brains of Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+
mice at 12, 15, 18 and 26 months of age using immunohistochemistry and thioflavin-S staining, as described in Materials and Methods. Our result shows no evidence of beta-amyloid plaques or neurofibrillary tangles in our mutant mice, although the transcriptional level of App
was increased by 50% in the mutant mice (26
). The reason for this difference between patients with DS and Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+
mice is currently unknown.
Although more than one gene may contribute to a DS phenotype, recent studies also suggest that, for some specific phenotypes, individual genes could be identified for playing the conspicuous roles by the gene-subtraction strategy (57
). In those experiments, a compound mutant was generated to carry a null allele of the gene and a triplicated Hsa21 syntenic region that often was Ts65Dn. The contribution of the gene to the phenotype was established based on elimination or significant alleviation of a DS-related phenotype observed in a segmentally trisomic mouse strain (57
). Because of the difference between Ts65Dn and Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+
mice, introducing the genotype of Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+
into the compound mutants in future gene-subtraction experiments would enable us to assess the role of an Hsa21 gene ortholog that is not triplicated in Ts65Dn.
The advance of chromosomal manipulation technologies has made it possible to establish the desired trans-species and segmental trisomic mouse models. These models should facilitate better understanding of the mechanisms underlying developmental cognitive disability in DS as well as the development of new therapies for this clinical phenotype of the disorder.