Trisomy 21 is a complex genetic insult and the only autosomal aneuploidy with a high frequency of postnatal survival in humans, affecting 1 in 750 live births. The diverse Down syndrome (DS) phenotypes include traits that are expressed in nearly all individuals with DS including mental retardation, distinct facial morphology, and Alzheimer-like pathology, in addition to numerous other traits that may or may not be expressed in an individual with DS [Van Cleve and Cohen, 2006; Van Cleve et al., 2006]. The specific genetic mechanisms responsible for producing the diverse complex phenotypes present in individuals with DS are unknown. Numerous genes have been proposed, with the ‘‘Down syndrome critical region’’(DSCR) model serving as the locus of debate. In general, this hypothesis posits that a dosage-sensitive gene or small subset of human chromosome (Hsa) 21 genes is responsible for many specific phenotypes of DS [Delabar et al., 1993; Korenberg et al., 1994]. This hypothesis was formulated from the study of a sample of individuals with trisomy for only part of Hsa21, who shared triplication of specific genes in a region extending from D21S55 to BCEI and also showed specific craniofacial anomalies. Direct testing of the role of 33 genes from this region demonstrated that ‘‘DSCR’’is a misnomer; these genes are not sufficient and are largely unnecessary to produce several prototypic phenotypes that were posited to map to this region [Olson et al., 2004, 2007].

Sumarsono et al.[1996] generated several lines ofEts2transgenic mice that constitutively expressed this transcription factor at relatively high levels in all tissues throughout development. These mice had skeletal anomalies that the authors equated to those in trisomy 16 mice and in humans with DS. Qualitative comparisons