Using mouse models to explore genotype-phenotype relationship in Down syndrome

Down Syndrome (DS) caused by trisomy 21 is characterized by a variety of phenotypes and involves multiple organs. Sequencing of human chromosome 21 (HSA21) and subsequently of its orthologues on mouse chromosome 16 have created an unprecedented opportunity to explore the complex relationship between various DS phenotypes and the extra copy of approximately 300 genes on HSA21. Advances in genetics together with the ability to generate genetically well-defined mouse models have been instrumental in understanding the relationships between genotype and phenotype in DS. Indeed, elucidation of these relationships will play an important role in understanding the pathophysiological basis of this disorder and helping to develop therapeutic interventions. A successful example of using such a strategy is our recent studies exploring the relationship between failed nerve growth factor (NGF) transport and amyloid precursor protein (App) overexpression. We found that increased dosage of the gene for App is linked to failed NGF signaling and cholinergic neurodegeneration in a mouse model of DS. Herein, we discuss several mouse models of DS and explore the emergence of exciting new insights into genotype-phenotype relationships, particularly those related to nervous system abnormalities. An important conclusion is that uncovering these relationships is enhanced by working from carefully defined phenotypes to the genes responsible.