Enhanced apoptosis during early neuronal differentiation in mouse ES cells with autosomal imbalance.
Although particular chromosomal syndromes are phenotypically and clinically distinct, the majority of individuals with autosomal imbalance, such as aneuploidy, manifest mental retardation. A common abnormal phenotype of Down syndrome (DS), the most prevalent autosomal aneuploidy, shows a reduction in both the number and the density of neurons in the brain. As a DS model, we have recently created chimeric mice from ES cells containing a single human chromosome 21. The mice mimicked the characteristic phenotypic features of DS, and ES cells showed a higher incidence of apoptosis during early neuronal differentiation in vitro. In this study, we examined the induction of anomalous early neural development by aneuploidy in mouse ES cells by transferring various human chromosomes or additional mouse chromosomes. Results showed an elevated incidence of apoptosis in all autosome-aneuploid clones examined during early neuronal differentiation in vitro. Further, cDNA microarray analysis revealed a common cluster of down-regulated genes, of which eight known genes are related to cell proliferation, neurite outgrowth and differentiation. Importantly, targeting of these genes by siRNA knockdown in normal mouse ES cells led to enhanced apoptosis during early neuronal differentiation. These findings strongly suggest that autosomal imbalance is associated with general neuronal loss through a common molecular mechanism for apoptosis.
Kai
Yoshiteru
Y
Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
Wang
Chi Chiu
CC
Kishigami
Satoshi
S
Kazuki
Yasuhiro
Y
Abe
Satoshi
S
Takiguchi
Masato
M
Shirayoshi
Yasuaki
Y
Inoue
Toshiaki
T
Ito
Hisao
H
Wakayama
Teruhiko
T
Oshimura
Mitsuo
M
D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002460:Cell Line; D002869:Chromosome Aberrations; D002891:Chromosomes, Human, Pair 21; D004314:Down Syndrome / Q000235:genetics; D015536:Down-Regulation; D047108:Embryonic Development / Q000502:physiology; D053595:Embryonic Stem Cells / Q000502:physiology*; D006801:Humans; D007621:Karyotyping; D051379:Mice; D046228:Microarray Analysis; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D010641:Phenotype; D034741:RNA, Small Interfering
D034741:RNA, Small Interfering