Gene network disruptions and neurogenesis defects in the adult Ts1Cje mouse model of Down syndrome.
BACKGROUND
Down syndrome (DS) individuals suffer mental retardation with further cognitive decline and early onset Alzheimer's disease.


RESULTS
To understand how trisomy 21 causes these neurological abnormalities we investigated changes in gene expression networks combined with a systematic cell lineage analysis of adult neurogenesis using the Ts1Cje mouse model of DS. We demonstrated down regulation of a number of key genes involved in proliferation and cell cycle progression including Mcm7, Brca2, Prim1, Cenpo and Aurka in trisomic neurospheres. We found that trisomy did not affect the number of adult neural stem cells but resulted in reduced numbers of neural progenitors and neuroblasts. Analysis of differentiating adult Ts1Cje neural progenitors showed a severe reduction in numbers of neurons produced with a tendency for less elaborate neurites, whilst the numbers of astrocytes was increased.


CONCLUSIONS
We have shown that trisomy affects a number of elements of adult neurogenesis likely to result in a progressive pathogenesis and consequently providing the potential for the development of therapies to slow progression of, or even ameliorate the neuronal deficits suffered by DS individuals.
Hewitt
Chelsee A
CA
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. Chelsee.Hewitt@Petermac.org
Ling
King-Hwa
KH
Merson
Tobias D
TD
Simpson
Ken M
KM
Ritchie
Matthew E
ME
King
Sarah L
SL
Pritchard
Melanie A
MA
Smyth
Gordon K
GK
Thomas
Tim
T
Scott
Hamish S
HS
Voss
Anne K
AK
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D064096:Aurora Kinase A; D064127:Aurora Kinases; D024682:BRCA2 Protein / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D053263:Gene Regulatory Networks / Q000235:genetics*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D064168:Minichromosome Maintenance Complex Component 7; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014314:Trisomy / Q000235:genetics
D024682:BRCA2 Protein; C106711:BRCA2 protein, mouse; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C491086:Mcm7 protein, mouse; D064168:Minichromosome Maintenance Complex Component 7