Human Molecular Genetics Advance Access originally published online on September 26, 2009
Human Molecular Genetics 2009 18(24):4756-4769; doi:10.1093/hmg/ddp438
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A new mouse model for the trisomy of the Abcg1–U2af1 region reveals the complexity of the combinatorial genetic code of down syndrome
1 Molecular Embryology and Immunology, Université d'Orléans, UMR6218, 45071 Orléans Cedex 2, France, 2 CNRS, UMR6218, MIE, 3B rue de la Férollerie, 45071 Orléans Cedex 2, France, 3 Genes and Disease Program, Center for Genomic Regulation, Dr Aiguader 88 and CIBER de Enfermedades Raras, 08003 Barcelona, Spain, 4 Department of Genetic Medicine and Development, University of Geneva Medical School, 1 Rue Michel-Servet, 1211 Geneva, Switzerland, 5 División de Neurociencias, Universidad Pablo de Olavide, Sevilla, Spain, 6 Key-Obs S.A., Allée du Titane, 45100 Orléans, France, 7 Service de Biochimie Métabolique, Hôpital Necker-Enfants Malades, Faculté de Médecine, Université, Paris Descartes 75730, France and 8 CNRS, UPS44, TAAM, Institut de Transgenose, 45071 Orleans Cedex 2, France
* To whom correspondence should be addressed at: UMR6218, IEM, Uni Orléans, CNRS, UPS44, TAAM, Institut de Transgénose, 3B rue de la Férollerie, 45071 Orléans Cedex 2, France. Tel: +33 238257976; Fax: +33 238255450; Email: herault{at}cnrs-orleans.fr
Received July 27, 2009; Accepted September 13, 2009
Mental retardation in Down syndrome (DS), the most frequent trisomy in humans, varies from moderate to severe. Several studies both in human and based on mouse models identified some regions of human chromosome 21 (Hsa21) as linked to cognitive deficits. However, other intervals such as the telomeric region of Hsa21 may contribute to the DS phenotype but their role has not yet been investigated in detail. Here we show that the trisomy of the 12 genes, found in the 0.59 Mb (Abcg1–U2af1) Hsa21 sub-telomeric region, in mice (Ts1Yah) produced defects in novel object recognition, open-field and Y-maze tests, similar to other DS models, but induces an improvement of the hippocampal-dependent spatial memory in the Morris water maze along with enhanced and longer lasting long-term potentiation in vivo in the hippocampus. Overall, we demonstrate the contribution of the Abcg1–U2af1 genetic region to cognitive defect in working and short-term recognition memory in DS models. Increase in copy number of the Abcg1–U2af1 interval leads to an unexpected gain of cognitive function in spatial learning. Expression analysis pinpoints several genes, such as Ndufv3, Wdr4, Pknox1 and Cbs, as candidates whose overexpression in the hippocampus might facilitate learning and memory in Ts1Yah mice. Our work unravels the complexity of combinatorial genetic code modulating different aspect of mental retardation in DS patients. It establishes definitely the contribution of the Abcg1–U2af1 orthologous region to the DS etiology and suggests new modulatory pathways for learning and memory.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.