title: Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down's syndrome: a gene expression study.
abstract: BACKGROUND
  Identification of genes and characterisation of their function is an essential step towards understanding complex pathophysiological abnormalities in Down's syndrome. We did a study to investigate abnormalities in gene expression in human neuronal stem cells and progenitor cells from Down's 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 Down's syndrome, and findings were compared with those of two control samples. Findings were validated against neurosphere preparations from three independent Down's syndrome fetuses and five independent controls by real-time quantitative PCR.
  
  
  RESULTS
  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 Down's 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 Down's syndrome stem-cell and progenitor-cell pool correlated with striking changes in neuron morphology after differentiation.
  
  
  CONCLUSIONS
  Our findings suggest a link between dysregulation of the REST transcription factor and some of the neurological deficits seen in Down's syndrome. Experimental REST downregulation has been shown to trigger apoptosis, which could account for the striking and selective loss of neurons in the differentiated Down's syndrome cell preparations.
authors.affiliation: Department of Neurobiology, Babraham Institute, Cambridge CB2 4AT, UK. sabine.bahn@bbsrc.ac.uk
authors.forename: Sabine
authors.initials: S
authors.lastname: Bahn
authors.forename: Michael
authors.initials: M
authors.lastname: Mimmack
authors.forename: Margaret
authors.initials: M
authors.lastname: Ryan
authors.forename: Maeve A
authors.initials: MA
authors.lastname: Caldwell
authors.forename: Eric
authors.initials: E
authors.lastname: Jauniaux
authors.forename: Michael
authors.initials: M
authors.lastname: Starkey
authors.forename: Clive N
authors.initials: CN
authors.lastname: Svendsen
authors.forename: Piers
authors.initials: P
authors.lastname: Emson
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004314:Down Syndrome / Q000235:genetics* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins; D008856:Microscopy, Fluorescence; D009414:Nerve Growth Factors / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D050777:Stathmin; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D008565:Membrane Proteins; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D012097:Repressor Proteins; D050777:Stathmin; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor; C063314:STMN2 protein, human