An Aneuploid Mouse Strain Carrying Human Chromosome 21 with Down Syndrome Phenotypes

Aideen O'Doherty; Sandra Ruf; Claire Mulligan; Victoria Hildreth; Mick L. Errington; Sam Cooke; Abdul Sesay; Sonie Modino; Lesley Vanes; Diana Hernandez; Jacqueline M. Linehan; Paul T. Sharpe; Sebastian Brandner; Timothy V. P. Bliss; Deborah J. Henderson; Dean Nizetic; Victor L. J. Tybulewicz; Elizabeth M. C. Fisher

doi:10.1126/science.1114535

Research Article

An Aneuploid Mouse Strain Carrying Human Chromosome 21 with Down Syndrome Phenotypes

Aideen O'Doherty1,3,
Sandra Ruf1,3,
Claire Mulligan4,
Victoria Hildreth5,
Mick L. Errington3,
Sam Cooke3,
Abdul Sesay3,
Sonie Modino6,
Lesley Vanes3,
Diana Hernandez1,3,
Jacqueline M. Linehan1,2,
Paul T. Sharpe6,
Sebastian Brandner1,
Timothy V. P. Bliss3,
Deborah J. Henderson5,
Dean Nizetic4,
Victor L. J. Tybulewicz3,*,
Elizabeth M. C. Fisher1,*

¹ Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London WC1N 3BG, UK.
² Medical Research Council Prion Unit, Institute of Neurology, Queen Square, London WC1N 3BG, UK.
³ National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
⁴ Centre for Haematology, Institute of Cell and Molecular Science, Barts and The London, Queen Mary's School of Medicine, 4 Newark Street, London E1 2AT, UK.
⁵ Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
⁶ Department of Craniofacial Development, Kings College London, Guy's Hospital, London SE1 9RT, UK.

↵* To whom correspondence should be addressed. E-mail: vtybule{at}nimr.mrc.ac.uk (V.L.J.T); e.fisher{at}prion.ucl.ac.uk (E.M.C.F.)

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Science 23 Sep 2005:
Vol. 309, Issue 5743, pp. 2033-2037
DOI: 10.1126/science.1114535

Aideen O'Doherty

Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London WC1N 3BG, UK. National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.

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Sandra Ruf

Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London WC1N 3BG, UK. National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.

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Claire Mulligan

Centre for Haematology, Institute of Cell and Molecular Science, Barts and The London, Queen Mary's School of Medicine, 4 Newark Street, London E1 2AT, UK.

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Victoria Hildreth

Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.

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Mick L. Errington

National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.

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Sam Cooke

National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.

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Abdul Sesay

National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.

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Sonie Modino

Department of Craniofacial Development, Kings College London, Guy's Hospital, London SE1 9RT, UK.

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Lesley Vanes

National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.

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Diana Hernandez

Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London WC1N 3BG, UK. National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.

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Jacqueline M. Linehan

Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London WC1N 3BG, UK. Medical Research Council Prion Unit, Institute of Neurology, Queen Square, London WC1N 3BG, UK.

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Paul T. Sharpe

Department of Craniofacial Development, Kings College London, Guy's Hospital, London SE1 9RT, UK.

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Sebastian Brandner

Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London WC1N 3BG, UK.

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Timothy V. P. Bliss

National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.

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Deborah J. Henderson

Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.

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Dean Nizetic

Centre for Haematology, Institute of Cell and Molecular Science, Barts and The London, Queen Mary's School of Medicine, 4 Newark Street, London E1 2AT, UK.

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Victor L. J. Tybulewicz

National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.

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Elizabeth M. C. Fisher

Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London WC1N 3BG, UK.

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Abstract

Aneuploidies are common chromosomal defects that result in growth and developmental deficits and high levels of lethality in humans. To gain insight into the biology of aneuploidies, we manipulated mouse embryonic stem cells and generated a trans-species aneuploid mouse line that stably transmits a freely segregating, almost complete human chromosome 21 (Hsa21). This “transchromosomic” mouse line, Tc1, is a model of trisomy 21, which manifests as Down syndrome (DS) in humans, and has phenotypic alterations in behavior, synaptic plasticity, cerebellar neuronal number, heart development, and mandible size that relate to human DS. Transchromosomic mouse lines such as Tc1 may represent useful genetic tools for dissecting other human aneuploidies.

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Mice carrying most of human chromosome 21 in each cell have developmental and learning difficulties similar to those found in Down's Syndrome, providing a way to study this disorder.

An Aneuploid Mouse Strain Carrying Human Chromosome 21 with Down Syndrome Phenotypes

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