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Down syndrome (DS) arises from triplication of genes on chromosome 21 (HSA21) and is characterized by neurological complications including cognitive dysfunction, epilepsy, and early onset Alzheimer’s disease (AD). At the histological and cellular level, DS brains show prolongation in the cell cycle length of neural progenitors, increased oxidative stress, and mitochondrial dysfunction. These pathological processes likely contribute to the observed decrease in neurogenesis, increased neuronal cell death, enhanced gliosis in the cortex, and a corresponding decrease in both neuronal glutamatergic and GABAergic expression. With recent advances in molecular biology and human genetics, many HSA21 genes have been identified, putative functions assigned to these genes and network analyses used to predict interconnecting, functional gene pathways. Interactions at this level are further complicated by gene regulatory mechanisms such as DNA methylation, histone acetylation and microRNA. In this respect, the neurological phenotypes seen in DS are not merely due to genomic imbalance from triplication of HSA21 genes, but also additive effects due to influences on associated genes within a given network or pathway and modification of gene expression due to epigenetic factors. The development of stem cell technologies has provided the opportunity to isolate human neural progenitors (HNPs) and induced pluripotent stem cells (iPS) from patients with known neurological disorders. These reagents are also used as tools to study molecular mechanisms and pharmacological therapies in various human diseases. They provide a means by which an understanding is established for interactions between various genes causal for a human disorder, especially in contiguous gene syndromes that are difficult to faithfully replicate in animal models. We have focused on the study of DS HNPs in relation to neurological phenotypes in the early onset of DS in these individuals. In the current review, we summarize the approaches taken, recent progress and insights gained from studies of DS during neural development, incorporating insights gained from the use of human DS neural progenitors.

Combinatorial Gene Effects on the Neural Progenitor Pool in Down Syndrome