Trisomy 21 is the cause of Down's syndrome (DS) which is characterized by a number of phenotypes, including a brain which is small and hypocellular compared to that of euploid individuals. The cerebellum is disproportionately reduced. Ts65Dn mice are trisomic for orthologs of about half of the genes on human chromosome 21 and provide a genetic model for DS. These mice display a number of developmental anomalies analogous to those in DS, including a small cerebellum with a significantly decreased number of both granule and Purkinje cell neurons. Here we trace the origin of the granule cell deficit to precursors in early postnatal development, which show a substantially reduced mitogenic response to Hedgehog protein signaling. Purified cultures of trisomic granule cell precursors show a reduced but dose-dependent response to the Sonic hedgehog protein signal in vitro , demonstrating that this is a cell-autonomous deficit. Systemic treatment of newborn trisomic mice with a small molecule agonist of Hedgehog pathway activity increases mitosis and restores granule cell precursor populations in vivo . These results demonstrate a basis for and a potential therapeutic approach to a fundamental aspect of CNS pathology in DS.

Down syndrome is a collection of features that are caused by trisomy for human Chromosome 21. While elevated transcript levels of the more than 350 genes on the chromosome are primarily responsible, it is likely that multiple genetic mechanisms underlie the numerous ways in which development and function diverge in individuals with trisomy 21 compared to euploid individuals. We consider genotype–phenotype interactions with the goal of producing working concepts that will be useful for approaches to ameliorate the effects of trisomy.

Ts65Dn is a mouse model of Down syndrome; a syndrome that results from Chromosome (Chr) 21 trisomy and is associated with congenital defects, cognitive impairment, and ultimately Alzheimer’s Disease. Ts65Dn mice have segmental trisomy for distal mouse Chr 16, a region sharing conserved synteny with human Chr 21. As a result, this strain harbors three copies of over half of the human Chr 21 orthologs. The trisomic segment of Chr 16 is present as a translocation chromosome (Mmu 1716), with breakpoints that have not been defined previously. To molecularly characterize the Chr 16 and Chr 17 breakpoints on the translocation chromosome in Ts65Dn mice, we used a selective enrichment and high-throughput, paired end sequencing approach. Analysis of paired end reads flanking the Chr 16, Chr 17 junction on Mmu1716 and de-novo assembly of the reads directly spanning the junction provided the precise locations of the Chr 16 and Chr 17 breakpoints at 84,351,351 bp and 9,426,822 bp, respectively. These data provide the basis for low cost, highly efficient genotyping of Ts65Dn mice. More importantly, these data provide, for the first time, complete characterization of gene dosage in Ts65Dn mice.