International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)

Oral Presentation

Tuesday 19 November

11:45 - 12:00 HRS


RJ Roper
Johns Hopkins University School of Medicine

Co-Authors: 1) Baxter LL, 1) Klinedinst DK, 2) Mullaney BC, 2,3) Blue ME, 1) Reeves RH
Institutions: 1) Johns Hopkins University School of Medicine, 2) Kennedy-Krieger Institute, 3) Johns Hopkins Medical Institute

Ts65Dn mice display many phenotypic similarities to Down syndrome (DS) including diminished cerebellar size.  We identified a reduction in granule cell (gc) density in the internal granule layer (IGL) in Ts65Dn mice and subsequently observed the same alteration in DS individuals (Hum Mol Genet, 9, 195-202).  To understand the etiology of these phenotypes, we compared cerebellar development of Ts65Dn and euploid mice between postnatal day 0 (P0) and P35.  Analysis of midline sagittal cerebellar sections revealed a reduction in size and IGL granule cell density beginning at P6 in Ts65Dn mice, and the external germinal layer (EGL), containing gc precursors that divide and migrate to populate the IGL, was diminished.  Unbiased stereological techniques were used to enumerate gc precursors and mitotic cells in the EGL at P0 and P6, demonstrating substantial differences in mitotic rate between trisomic and euploid mice.  To explore the molecular mechanism for the mitotic deficit, we examined Ts65Dn and euploid mice carrying a lacZ knock-in at the Ptc locus; Ptc expression is activated by sonic hedgehog (shh), a significant mitogen for gc precursors.  lacZ protein was higher in euploid than in Ts65Dn mice at P6, implicating the shh pathway in the Ts65Dn granule cell deficiency.  Beginning with a phenotype of adult DS cerebellum, we observed a parallel anomaly in mice, identified the cellular basis for this problem in mice which predicted the human situation, determined an early postnatal developmental problem in generation of these cells, and implicated the shh molecular pathway in the deficiency.

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