Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Downʹs syndrome: a gene expression study

Background Identification of genes and characterisation of their function is an essential step towards understanding complex pathophysiological abnormalities in Downʹs syndrome. We did a study to investigate abnormalities in gene expression in human neuronal stem cells and progenitor cells from Downʹs syndrome and control post-mortem human fetal tissue. Methods Indexing-based differential display PCR was done on neuronal precursor cells derived from the cortex of a fetus with Downʹs syndrome, and findings were compared with those of two control samples. Findings were validated against neurosphere preparations from three independent Downʹs syndrome fetuses and five independent controls by real-time quantitative PCR. Findings Results of differential display PCR analysis showed that SCG10—a neuron-specific growth-associated protein regulated by the neuron-restrictive silencer factor REST—was almost undetectable in the Downʹs syndrome sample. This finding was validated by real-time PCR. We also found that other genes regulated by the REST transcription factor were selectively repressed, whereas non-REST-regulated genes with similar functions were unaffected. Changes in expression of several key developmental genes in the Downʹs syndrome stem-cell and progenitor-cell pool correlated with striking changes in neuron morphology after differentiation. Interpretation Our findings suggest a link between dysregulation of the REST transcription factor and some of the neurological deficits seen in Downʹs syndrome. Experimental REST downregulation has been shown to trigger apoptosis, which could account for the striking and selective loss of neurons in the differentiated Downʹs syndrome cell preparations.