| Down syndrome (DS), caused by trisomy 21, is the most common live-born human aneuploidy. The mechanism by which dosage imbalance of chromosome 21 genes disrupts development is only now starting to be understood. In this work, we used microarrays to analyze the cerebellar transcriptome of the Ts65Dn mouse model of DS, identified a trisomic cerebellar granule cell deficit in response to Sonic hedgehog (SHH) and characterized that deficit at the transcriptional level.; In the adult Ts65Dn cerebellum, triplicated genes were, on average, overexpressed 1.5-fold. Additionally, trisomic and euploid transcriptomes were robustly distinguished by cluster analysis. While changes in expression of individual genes were subtle, differences in the transcriptomes extended deeply into a set of thousands of probes throughout the genome.; We showed a deficit in the response of developing Ts65Dn granule cell precursors (gcp) to the mitogenic effects of SHH, which then contributes to the reduction in cell number not observed at birth but significant by postnatal day (P) 6. Although at a lower level, trisomic gcp, like euploid, did respond to SHH, leading us to test and successfully demonstrate an in vivo effect of a SHH agonist in rescuing the Ts65Dn gcp deficit by P6.; To understand the basis of the difference between the trisomic and euploid cell response to SHH, we performed another microarray analysis, on P6 gcp. Cluster analysis distinguished trisomic from euploid, confirming our observations in adult cerebella, that trisomy results in a global alteration of the transcriptome. Further, within these groups, SHH-treated and untreated samples were clustered separately. Additionally, we showed that SHH induced the transcription of genes involved in cell cycle progression, DNA replication and differentiation, in both euploid and trisomic cells. However, the transcriptional response in the trisomic cells was significantly lower. Further, we identified genes that were activated only in trisomic gcp, perhaps contributing to their deficient response.; Collectively, this work extends our understanding of the adult and developing DS cerebellum. It also presents the first link between SHH and a trisomy-induced phenotype, offering a potential avenue for DS therapy. |
