Abstract
BackgroundDown syndrome (DS), caused by trisomy of human chromosome 21 (HSA21), is the most common genetic cause of mental retardation in humans. Among complex phenotypes, it displays a number of neural pathologies including smaller brain size, reduced numbers of neurons, reduced dendritic spine density and plasticity, and early Alzheimer-like neurodegeneration. Mouse models for DS show behavioural and cognitive defects, synaptic plasticity defects, and reduced hippocampal and cerebellar neuron numbers. Early postnatal development of both human and mouse-model DS shows the reduced capability of neuronal precursor cells to generate neurons. The exact molecular cause of this reduction, and the role played by increased dosage of individual HSA21 genes, remain unknown.ResultsWe have subcutaneously injected mouse pluripotent ES cells containing a single freely segregating supernumerary human chromosome 21 (HSA21) into syngeneic mice, to generate transchromosomic teratomas. Transchromosomic cells and parental control cells were injected into opposite flanks of thirty mice in three independent experiments. Tumours were grown for 30 days, a time-span equivalent to combined intra-uterine, and early post-natal mouse development. When paired teratomas from the same animals were compared, transchromosomic tumours showed a three-fold lower percentage of neuroectodermal tissue, as well as significantly reduced mRNA levels for neuron specific (Tubb3) and glia specific (Gfap) genes, relative to euploid controls. Two thirds of transchromosomic tumours also showed a lack of PCR amplification with multiple primers specific for HSA21, which were present in the ES cells at the point of injection, thus restricting a commonly retained trisomy to less than a third of HSA21 genes.ConclusionWe demonstrate that a supernumerary chromosome 21 causes Inhibition of Neuroectodermal DIfferentiation (INDI) of pluripotent ES cells. The data suggest that trisomy of less than a third of HSA21 genes, in two chromosomal regions, might be sufficient to cause this effect.
Highlights
Down syndrome (DS), caused by trisomy of human chromosome 21 (HSA21), is the most common genetic cause of mental retardation in humans
In an attempt to study the effects of trisomy 21 on the capacity of pluripotent embryonic stem (ES) cells to proliferate and differentiate in vivo, we report here the use of a mouse pluripotent embryonic stem (ES) cell line with a freely segregating HSA21 as a single supernumerary chromosome [24], in the generation of transchromosomic teratomas upon subcutaneous injections into syngeneic mice
Generation of teratomas The cell line (47-1), generated by introduction of a single HSA21 into the mouse ES cell line D3, was found by PCR amplification of human specific markers to contain virtually all of the gene content of HSA21, and was shown not to contain DNA from any human chromosome other than HSA21 [24]
Summary
Down syndrome (DS), caused by trisomy of human chromosome 21 (HSA21), is the most common genetic cause of mental retardation in humans. Among complex phenotypes, it displays a number of neural pathologies including smaller brain size, reduced numbers of neurons, reduced dendritic spine density and plasticity, and early Alzheimer-like neurodegeneration. Down's syndrome (DS), caused by the trisomy of human chromosome 21 (HSA21), [1] is a complex condition characterized by a plethora of phenotypic features, most striking of which are reduced neuron number and synaptic plasticity, early Alzheimer-like neurodegeneration, craniofacial dysmorphia, heart development defects, and powerful suppression of the incidence of most solid tumours [2,3]. Tumours of neural tissues, such as neuroblastomas, are comparatively very rarely observed in DS individuals [9,10]
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