International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 151 - A ROLE FOR SONIC HEDGEHOG IN THE CEREBELLAR DEFICITS OF THE TS65DN MOUSE MODEL OF DOWN SYNDROME

Saran NG, Klinedinst DK, Roper RJ, Baxter LL, Beachy PA, Reeves RH

Johns Hopkins University School of Medicine, Baltimore, United States

Down syndrome (DS), the most common viable autosomal aneuploidy in humans, is caused by trisomy 21. The Ts65Dn mouse is a model with segmental trisomy for approximately 16 Mb at the distal end of mouse chromosome 16 in a region that shows near-perfect conserved synteny with human chromosome 21, and includes orthologs of about half the chromosome 21 genes. Like humans with DS, the Ts65Dn mouse has a significantly reduced cerebellum and reduced density of Purkinje and granule cells that comprise the internal granule layer of the cerebellum. We present a postnatal profile of the maldevelopment in the granule cells that identifies the developmental stage at which the trisomy-related morphological differences first appear. We also show that the granule cell precursors (gcp) are the affected cell population. Further, we investigate the effects of sonic hedgehog (Shh), a potent mitogen that activates transcription of several genes in gcp. We show reduced activation of genes whose transcription is regulated by Shh and a reduced yet dose-dependent response of the trisomic gcp to the Shh-induced mitogenic pathway. This deficit underlies the insufficient generation of granule cells seen in Ts65Dn mice. Using gene expression data from trisomic and euploid gcp stimulated by Shh, we are analyzing the basis for this cell-autonomous response deficit.

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