ld be mapped in mouse. Similarly, although it is known that Mx maps to mouse chromosome 16 and Tff3, Cbs and Crya map to mouse chromosome 17, there are 11 genes between and among these that are of unknown map location in mouse. Lastly, PDXK is the most proximal chromosome 21 gene mapped to mouse chromosome 10 . Genes in this region are relatively small, however, and additional chromosome 21 genes may be located on mouse chromosome 10 between Pdxk and the adjacent region homologous with human chromosome 19. Defining the endpoints of these homologous regions is critical for evaluating gene-phenotype correlations within existing mouse models and for designing new ones.
Currently, the best mouse models of DS are the mouse chromosome 16 segmental trisomies, Ts65Dn and Ts1Cje. Ts65Dn is trisomic for the region spanning an undefined distance proximal to App through Mx to presumably the telomere of chromosome 16. The phenotype of Ts65Dn includes working memory impairment and long term memory deficits; delayed development and lower body weight; motor dysfunction; decreased responsiveness to pain; hyperactivity; and decreased ability to inhibit behavior (reviewed in [30,31]; see also [32,33]). Particularly interesting are observations of age-related loss of cholinergic neurons, decreased numbers of asymmetric synapses in the temporal cortex, abnormalities in neuron number in hippocampal regions, and deficiencies of beta-noradrenergic transmission within the hippocampus and cerebral cortex [34,35,36,37,38]. Some of these deficits have been observed in DS; others suggest new avenues of investigation. Knowing which genes cannot be responsible for the phenotype can be helpful. Table Table3a3a lists the 32 genes found centromeric to the Alzheimer's-associated gene APP on chromosome 21. On the basis of current comparative mapping data, most of these may be present in only two copies in Ts65Dn and therefore would not contribute to its phenotypic features. The Ts1Cje mouse is a more recent model, and is trisomic for the region of mouse chromosome 16 from Sod1 through Mx (and again presumably to the telomere). While it has not yet been studied so thoroughly as Ts65Dn, there are phenotypic differences between the two mice. In contrast to Ts65Dn, Ts1Cje shows hypoactivity, no loss of cholinergic neurons, and no deficits in the visible platform part of the water maze tests (which tests only memory and not the ability to make spatial correlations) . Table Table3b3b lists 27 genes that are expected to be trisomic in the Ts65Dn but only disomic in the Ts1Cje, based on the genetic map . It is tempting to conclude that these genes must account for the phenotypic differences, but it must be kept in mind that the two mouse strains have been produced on different genetic backgrounds, which may have phenotypic consequences.
Segmental trisomies for the regions of chromosome 21 homologous with mouse chromosomes 17 and 10 do not exist. If Mx is the most telomeric gene on mouse chromosome 16 and Pdxk is the most centromeric on mouse chromosome 10, there are 33 genes within the approximately 2.2 Mb of the mouse chromosome 17 region (Table (Table4)4) and 50 genes within the approximately 2.9 Mb of the mouse chromosome 10 region. Adding the maximum of 32 genes not trisomic in the Ts65Dn, half of the chromosome 21 homologous genes are not trisomic in Ts65Dn. The phenotypic consequences of these genes must be assessed in some fashion, because the Ts65Dn lacks some features of DS. Constructing single-gene transgenic mice expressing each of these and then combining each with the Ts65Dn by breeding would be laborious and probably of limited success. An alternative is to generate additional segmental trisomies using the Cre-lox system .
Analysis of the complete sequence of chromosome 21 has provided the first look at all candidate DS genes. The next steps require verifying and refining the predicted, incomplete gene models, defining new models as necessary, and isolating complete cDNAs for each gene. With complete coding sequences, protein sequences can be examine