Genomic and functional profiling of human Down syndrome neural progenitors implicates S100B and aquaporin 4 in cell injury.
Down syndrome (DS) is caused by trisomy of chromosome 21 and is characterized by mental retardation, seizures and premature Alzheimer's disease. To examine neuropathological mechanisms giving rise to this disorder, we generated multiple human DS neural progenitor cell (NPC) lines from the 19-21 week frontal cortex and characterized their genomic and functional properties. Microarray profiling of DS progenitors indicated that increased levels of gene expression were not limited to chromosome 21, suggesting that increased expression of genes on chromosome 21 altered transcriptional regulation of a subset of genes throughout the entire genome. Moreover, many transcriptionally dysregulated genes were involved in cell death and oxidative stress. Network analyses suggested that upregulated expression of chromosome 21 genes such as S100B and amyloid precursor protein activated the stress response kinase pathways, and furthermore, could be linked to upregulation of the water channel aquaporin 4 (AQP4). We further demonstrate in DS NPCs that S100B is constitutively overexpressed, that overexpression leads to increased reactive oxygen species (ROS) formation and activation of stress response kinases, and that activation of this pathway results in compensatory AQP4 expression. In addition, AQP4 expression could be induced by direct exposure to ROS, and siRNA inhibition of AQP4 resulted in elevated levels of ROS following S100B exposure. Finally, elevated levels of S100B-induced ROS and loss of AQP4 expression led to increased programmed cell death. These findings suggest that dysregulation of chromosome 21 genes in DS neural progenitors leads to increased ROS and thereby alters transcriptional regulation of cytoprotective, non-chromosome 21 genes in response to ongoing cellular insults.
Esposito
Giuseppe
G
Department of Human Physiology and Pharmacology, Vittorio Erspamer Faculty of Pharmacy, University of Rome La Sapienza, Rome, Italy.
Imitola
Jaime
J
Lu
Jie
J
De Filippis
Daniele
D
Scuderi
Caterina
C
Ganesh
Vijay S
VS
Folkerth
Rebecca
R
Hecht
Jonathan
J
Shin
Soojung
S
Iuvone
Teresa
T
Chesnut
Jonathan
J
Steardo
Luca
L
Sheen
Volney
V
D017209:Apoptosis; D051401:Aquaporin 4 / Q000235:genetics* / Q000378:metabolism*; D001483:Base Sequence; D016022:Case-Control Studies; D002460:Cell Line; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004314:Down Syndrome / Q000196:embryology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D053595:Embryonic Stem Cells / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D039904:Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
C496030:AQP4 protein, human; D051401:Aquaporin 4; D017931:DNA Primers; D009414:Nerve Growth Factors; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human