Elevated apoptosis in pre-mature neurons differentiated from mouse ES cells containing a single human chromosome 21.
A decrease in the number and density of neurons is the most common phenotype in the brains of Down syndrome (DS) patients, causing mental retardation. Studies using primary cultured neurons from DS patients or from model mice have suggested that a defect in metabolism of reactive oxygen species, or diminished levels of glutathione, causes mitochondrial and caspase-mediated neuronal apoptosis in vitro. However, it is not well documented whether neuronal apoptosis also occurs in immature DS neurons, owing to the difficulty in isolating or identifying neuronal stem cells in human or mouse fetuses. Here we utilized an in vitro model system for neuronal differentiation, with mouse embryonic stem cells containing human chromosome 21 (TT2F/hChr.21) to examine the effect of an additional hChr.21 on the early phases of neurogenesis. The differentiation profile of TT2F/hChr.21 cells was essentially the same as those of parental TT2F ES cells. In differentiations of both TT2F and TT2F/hChr.21 cells, high level of apoptosis was observed in neuronal stem cells, but the rate of apoptosis in TT2F/hChr.21 cells was significantly higher than that of parental cells. These results suggest that quantitative changes in the level of apoptosis in DS neuronal stem cells may account for the reduction of neuronal number and density in the DS brain.
Kadota
Mitsutaka
M
Division of Molecular and Cell Genetics, Department of Molecular and Cellular Biology, Faculty of Medicine, School of Life Sciences, Tottori University, Nishimachi 86, Yonago, Tottori 683-8503, Japan.
Shirayoshi
Yasuaki
Y
Oshimura
Mitsuo
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015415:Biomarkers; D002454:Cell Differentiation / Q000502:physiology*; D002469:Cell Separation; D002478:Cells, Cultured; D002891:Chromosomes, Human, Pair 21 / Q000502:physiology*; D003114:Colony-Forming Units Assay; D004314:Down Syndrome / Q000235:genetics / Q000503:physiopathology; D004622:Embryo, Mammalian / Q000166:cytology; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D007621:Karyotyping; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*
D015415:Biomarkers