International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


POSTER 161 - MINIMAL TRANSCRIPT LEVEL CHANGES IN THE CEREBELLUM OF A MOUSE GENETIC MODEL FOR DOWN SYNDROME

N Saran
Dept of Physiology, Johns Hopkins School of Medicine

1) Pletcher M, 2) Natale J, 1) Reeves R
1) Johns Hopkins School of Medicine, Baltimore, MD 2) Children’s Hospital, Washington, DC

Trisomy 21 results in Down Syndrome (DS), the most common genetic cause of mental retardation. Ts65Dn (Ts) mice are at dosage imbalance for about half of the genes on Chr21. They demonstrate significant reduction in cerebellar volume, as do DS individuals. Histological analysis identified specific changes that correctly predicted alterations in DS brains (Baxter et al., 2000). We compared transcript profiles in five Ts mice and five euploid (Eu) littermates in duplicate on Affymetrix U74A chips. We used the CLUSTER program (Eisen et al., 1998) to sort all experiments and analysed the three pairs where the duplicates were most closely matched. The resulting trees grouped Ts separately from Eu mice, i.e., gene expression profiles discriminated between the two groups. No one functional category of genes was evident. Only 25 of 6601 probes varied by 2-fold or more in either direction, and only 171 showed a 1.5-fold change, where half increased and half decreased; nine of the 18 human Chr21 homologs on the chip increased 1.5-fold. The predominant cell type in the cerebellum is the granule cell (gc) neuron, representing 50% of neurons in adult brains. Therefore, we primarily measured gc transcript levels. Despite significant changes in gc number and the architecture of the internal granule layer, only subtle differences in expression distinguish Ts from Eu neurons. Thus, at the transcript level, neurons that survive to adulthood are relatively normal; gene dosage effects of trisomy may be more pronounced in the developmental processes that produce the adult structure.


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