Molecular genetics and brain in the Tc1 mouse model of Down syndrome
Lead Research Organisation:
University College London
Department Name: Institute of Neurology
Abstract
Babies with Down syndrome account for about 1 in 700 births. The syndrome arises because people with Down syndrome have an extra copy of chromosome 21. Down syndrome is the most common known cause of mental retardation, and occurs along with many other more variable features, such as specific heart defects or abnormalities of the immune system.
To try to find out which genes on human chromosome 21 give rise to the different aspects of the syndrome, we created a mouse model of Down syndrome. This is a unique mouse strain, and it does recapitulate the features of Down syndrome.
We are now applying for funding to work out exactly which genes are present in this mouse, and when and where they are switched on. We then want to refine the mouse model by adding in a marker that allows us to tell which cells contain the extra chromosome. We also want to go to study the brain of these mice, to see how closely the mouse parallels human Down syndrome, and ultimately to try to work out which are the important genes for producing some of the specific brain changes that are seen in Down syndrome.
This research will help us understand more about why Down syndrome occurs, with a long-term view to therapy for some aspects of the syndrome, and will also tell us about exactly the same disorders that occur in the non-Down syndrome population.
To try to find out which genes on human chromosome 21 give rise to the different aspects of the syndrome, we created a mouse model of Down syndrome. This is a unique mouse strain, and it does recapitulate the features of Down syndrome.
We are now applying for funding to work out exactly which genes are present in this mouse, and when and where they are switched on. We then want to refine the mouse model by adding in a marker that allows us to tell which cells contain the extra chromosome. We also want to go to study the brain of these mice, to see how closely the mouse parallels human Down syndrome, and ultimately to try to work out which are the important genes for producing some of the specific brain changes that are seen in Down syndrome.
This research will help us understand more about why Down syndrome occurs, with a long-term view to therapy for some aspects of the syndrome, and will also tell us about exactly the same disorders that occur in the non-Down syndrome population.
Technical Summary
DS is the most common known form of mental retardation, and also has at least 80 other phenotypic aspects in different tissues. We have created a unique mouse model of DS, the Tc1 transchromosomic mouse. We now wish to investigate the molecular genetics of this mouse in detail and to go on to improve the model and start to study the brain in this animal.
Organisations
- University College London, United Kingdom (Collaboration, Lead Research Organisation)
- Mouse Clinical Institute (Collaboration)
- Queen Mary, University of London, United Kingdom (Collaboration)
- University of Cambridge (Collaboration)
- Cardiff University, United Kingdom (Collaboration)
- Johnson & Johnson Ltd, United Kingdom (Collaboration)
- University of Queensland, Australia (Collaboration)
- Birkbeck, University of London (Collaboration)
- Francis Crick Institute (Collaboration)
- Medical Research Council (Collaboration)
Publications

Ahmed MM
(2013)
Protein profiles in Tc1 mice implicate novel pathway perturbations in the Down syndrome brain.
in Human molecular genetics

Alford KA
(2010)
Perturbed hematopoiesis in the Tc1 mouse model of Down syndrome.
in Blood

Canzonetta C
(2008)
DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.
in American journal of human genetics

Choong X
(2013)
P1-106: Using primary neurons from transgenic mice to identify genes on human chromosome 21 influencing Alzheimer's neuropathology
in Alzheimer's & Dementia

Choong XY
(2015)
Dissecting Alzheimer disease in Down syndrome using mouse models.
in Frontiers in behavioral neuroscience

Cleary JO
(2011)
Structural correlates of active-staining following magnetic resonance microscopy in the mouse brain.
in NeuroImage

Cleverley K
(2021)
A novel knockout mouse for the small EDRK-rich factor 2 (Serf2) showing developmental and other deficits.
in Mammalian genome : official journal of the International Mammalian Genome Society



Dekker AD
(2017)
Aging rather than aneuploidy affects monoamine neurotransmitters in brain regions of Down syndrome mouse models.
in Neurobiology of disease
Description | Down syndrome research in UK |
Geographic Reach | National |
Policy Influence Type | Gave evidence to a government review |
Description | ART Research Grant |
Amount | £30,000 (GBP) |
Organisation | Alzheimer's Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2009 |
End | 12/2011 |
Description | AlzSoc PhD studentship Investigating cellular changes in Down syndrome that predispose to Alzheimer disease |
Amount | £91,000 (GBP) |
Organisation | Alzheimer's Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2017 |
End | 09/2020 |
Description | Alzheimer's Research UK PhD Studentship |
Amount | £105,000 (GBP) |
Organisation | Alzheimer's Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2013 |
End | 09/2016 |
Description | Alzheimer's Society PhD studentship |
Amount | £84,990 (GBP) |
Organisation | Alzheimer's Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2014 |
End | 09/2017 |
Description | Biochemical Society Summer Vacation Studentship |
Amount | £1,600 (GBP) |
Organisation | Biochemical Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 05/2013 |
End | 07/2013 |
Description | Pilot Project ERUK |
Amount | £29,897 (GBP) |
Organisation | Epilepsy Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 07/2013 |
End | 03/2014 |
Description | Senior Investigator Award |
Amount | £1,741,765 (GBP) |
Funding ID | 098328 |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2014 |
End | 12/2022 |
Description | Synaptic, Cellular and Neural Circuit Dysfunction in Down Syndrome |
Amount | £2,444,366 (GBP) |
Funding ID | 217199/Z/19/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2019 |
End | 08/2024 |
Description | Using mouse models to understand altered inflammation in Down syndrome dementia |
Amount | £910,000 (GBP) |
Organisation | Alzheimer's Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2020 |
End | 09/2023 |
Description | Wellcome Trust Joint Senior Investigators Award |
Amount | £1,258,000 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2013 |
End | 12/2019 |
Description | Wellcome Trust Strategic Award |
Amount | £838,000 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2013 |
End | 12/2017 |
Title | A panel of mice with partial trisomies, with Dr Victor Tybulewicz |
Description | Panel of 12 new mouse strains for modelling human Down syndrome and finding genes underlying the syndrome |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2015 |
Provided To Others? | Yes |
Impact | Papers and new research collaborations and new research in external groups. Also depositing the mice in the European Mutant Mouse Archive so they are freely available to others. |
Title | Mouse models of Down Syndrome |
Description | We have generated 14 new mouse strains with duplications or deletions of large regions of mouse chromosomes orthologous to human chromosome 21. |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2016 |
Provided To Others? | Yes |
Impact | Multiple collaborations and requests for use of the animals. |
Title | Tc1 mice |
Description | Mouse model of Down syndrome |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Provided To Others? | Yes |
Impact | Allow study of Down syndrome |
URL | http://www.ncbi.nlm.nih.gov/pubmed/16179473 |
Title | Chromosome 21 map |
Description | Interactive chromosome 21 map that shows human sequences and mouse homologs, and shows breakpoints for the various engineered mouse partial trisomy strains. Ours and others. |
Type Of Material | Database/Collection of data |
Year Produced | 2013 |
Provided To Others? | Yes |
Impact | Offered to various research groups internationally, but need an informatics curator, which we do not have. |
Description | Analysing the metabolome Griffin, Cambridge |
Organisation | University of Cambridge |
Department | Department of Earth Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Access to novel mice and mouse crosses |
Collaborator Contribution | Analysis of the metabolome including lipidomics |
Impact | No outputs yet |
Start Year | 2016 |
Description | Cardiff DS mouse models behaviour |
Organisation | Cardiff University |
Department | School of Psychology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Mouse models of Down syndrome and Alzheimers disease |
Collaborator Contribution | In depth behavioural analysis |
Impact | Papers and research |
Start Year | 2014 |
Description | Down Syndrome |
Organisation | University College London |
Department | Institute of Neurology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Joint grant applications, joint research program, joint publications |
Collaborator Contribution | Joint grant applications, joint research program, joint publications |
Impact | PMID: 16987872; PMID: 18047653; PMID: 18626093; PMID: 18771760; PMID: 18787134; PMID: 19001410; PMID: 19181682; PMID: 19726804; PMID: 20154221; PMID: 20535211; PMID: 20697343. |
Description | Down syndrome and cancer |
Organisation | Queen Mary University of London |
Department | Barts Cancer Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Contributing mouse resources and expertise in pathology |
Collaborator Contribution | Expertise in cancer and angiogenesis |
Impact | Papers and ongoing research. |
Start Year | 2009 |
Description | Down syndrome and heart development |
Organisation | Medical Research Council (MRC) |
Department | MRC National Institute for Medical Research (NIMR) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Mouse resources and a postdoc |
Collaborator Contribution | Expertise in heart development and imaging |
Impact | Papers, new experimental paradigms, studentships |
Start Year | 2008 |
Description | Engineering new mouse models of Down syndrome |
Organisation | Medical Research Council (MRC) |
Department | MRC National Institute for Medical Research (NIMR) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Research ideas input and resources such as mouse tissues and crosses. |
Collaborator Contribution | Intellectual input and a wider base of collaborators to help analyse our mice. |
Impact | Publications, joint grants, a PhD student. |
Description | Heart development in Down Syndrome |
Organisation | Medical Research Council (MRC) |
Department | MRC National Institute for Medical Research (NIMR) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Mice, joint research planning |
Collaborator Contribution | Joint publication. PMID: 20558441 |
Impact | PMID: 20558441 |
Description | Imaging |
Organisation | University College London |
Department | Centre for Advanced Bioimaging |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Mouse models |
Collaborator Contribution | High resolution imaging |
Impact | Papers, studentships. |
Start Year | 2006 |
Description | International requests for Tc1 and other Down syndrome model mice. |
Organisation | Francis Crick Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We created and phenotyped and published the animals, mouse models of Down syndrome. |
Collaborator Contribution | We periodically receive direct requests for various of these Down syndrome model mice from national and international laboratories, based on information in our publications. The mice are freely available from repositories such as EMMA and Jax, and so requests do not need to come through us, but it is notable that these mice are of wide interest to the research community. |
Impact | Different labs, different research interests. Note that in sending mice we are NOT embarking on a formal collaboration. |
Start Year | 2007 |
Description | LonDowns |
Organisation | Birkbeck, University of London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Six labs working jointly to understand the link between alzheimer disease and down syndrome. |
Collaborator Contribution | We bring in mouse expertise, which is compared with the groups studying infants and adults with down syndrome, and also with cell models and genetics of people with down syndrome. |
Impact | Major meeting taking place in 2014 that we are organising. |
Start Year | 2013 |
Description | LonDowns |
Organisation | Medical Research Council (MRC) |
Department | MRC National Institute for Medical Research (NIMR) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Six labs working jointly to understand the link between alzheimer disease and down syndrome. |
Collaborator Contribution | We bring in mouse expertise, which is compared with the groups studying infants and adults with down syndrome, and also with cell models and genetics of people with down syndrome. |
Impact | Major meeting taking place in 2014 that we are organising. |
Start Year | 2013 |
Description | LonDowns |
Organisation | Queen Mary University of London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Six labs working jointly to understand the link between alzheimer disease and down syndrome. |
Collaborator Contribution | We bring in mouse expertise, which is compared with the groups studying infants and adults with down syndrome, and also with cell models and genetics of people with down syndrome. |
Impact | Major meeting taking place in 2014 that we are organising. |
Start Year | 2013 |
Description | Looking at gliosis in neurodegeneration |
Organisation | University of Queensland |
Country | Australia |
Sector | Academic/University |
PI Contribution | Access to unique mouse models and crosses |
Collaborator Contribution | Analysis of gliosis and potentially the inflammasome |
Impact | No outputs yet |
Start Year | 2017 |
Description | Mouse Aß species and trisomy of chromosome 21 |
Organisation | Johnson & Johnson |
Department | Janssen Pharmaceuticals |
Country | United States |
Sector | Private |
PI Contribution | Based on our finding that trisomy of chromosome 21 exacerbates the accumulation of Abeta in the brain, we have supplied mouse brain tissues from our models for an investigation of the accumulation of mouse Abeta in brain. |
Collaborator Contribution | Highly sensitive mouse Abeta ELISA. |
Impact | Data generated from this collaboration has furthered our understanding of the effect of trisomy of chromosome 21 on the development of Alzheimer's disease. |
Start Year | 2013 |
Description | Mouse mapping zoo |
Organisation | Mouse Clinical Institute |
Country | France |
Sector | Academic/University |
PI Contribution | Mouse resources for mapping genes involved in Down syndrome. |
Collaborator Contribution | Mouse resources for mapping genes involved in Down syndrome. |
Impact | Papers, grants. |
Start Year | 2006 |
Description | NIMR and mouse engineering |
Organisation | Medical Research Council (MRC) |
Department | MRC National Institute for Medical Research (NIMR) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | a postdoc, grant funding, expertise. |
Collaborator Contribution | expertise in manipulating ES cells. |
Impact | grant and papers |
Description | Prion collaboration |
Organisation | University College London |
Department | MRC Prion Unit |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Mouse resources, neurodegeneration expertise |
Collaborator Contribution | molecular biology expertise |
Impact | Papers |
Start Year | 2011 |
Description | Transcription analysis in mouse model of Down syndrome |
Organisation | University of Cambridge |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Access to mouse tissues. |
Collaborator Contribution | Entirely novel approach to analysing the biology of our mouse model of Down syndrome. |
Impact | So far, PMID: 18787134 |
Start Year | 2007 |
Description | electrophysiology of DS and AD-DS mice (Pishan/Walker) |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | A unique panel of mice that model human Down syndrome and allow us to map genes |
Collaborator Contribution | Expertise in EEG and behaviour, and therefore the ability to determine behaviour and see how aberrations correlate with EEG in our different models. |
Impact | No outputs yet. |
Start Year | 2016 |
Title | New mouse trisomy models |
Description | New mouse strains subject to Material Transfer Agreements. |
IP Reference | |
Protection | Copyrighted (e.g. software) |
Year Protection Granted | 2011 |
Licensed | Yes |
Impact | Papers should come out of using thise resource. |
Description | 2019 Down syndrome day event |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | World Down Syndrome Day event, organised with talks, activities, refreshments, for people with Down syndrome and their carers to meet to understand our research and hear updates. |
Year(s) Of Engagement Activity | 2019 |
Description | Co-organised Keystone Meeting on the Biology of Down syndrome. |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | An academic meeting on DS and AD, but it included representatives from several charity and government funders. |
Year(s) Of Engagement Activity | 2016 |
Description | Crick talk |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Talk to general public interested in our research. |
Year(s) Of Engagement Activity | 2015 |
Description | DS Lay talk, Cardiff |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Presentation of our work to a patient and carer group. |
Year(s) Of Engagement Activity | 2015 |
Description | Down Syndrome Cognition Workshop |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | International |
Primary Audience | Participants in your research and patient groups |
Results and Impact | Highly specialist audience. Chaired session and lab and collaborators presented several posters. Audience consisted of scientists and also parent organisations and interested lay people from the Down syndrome community. Disseminating our research, presenting our work to a North American lay audience who did not know about it, making the point that our mouse model is freely available worldwide. |
Year(s) Of Engagement Activity | 2013 |
URL | http://finance.yahoo.com/news/linda-crnic-institute-down-syndrome-221500144.html |
Description | Down syndrome association annual meeting |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | Yes |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Talk to audience of people with Down syndrome and their families and the UK Down syndrome association Raising research as an issue for the public to join in with. |
Year(s) Of Engagement Activity | 2007 |
Description | Funders visit |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | approximately 5 lay members from a dementia association attended two talks from our group to present our work to them. |
Year(s) Of Engagement Activity | 2015 |
Description | Interviewed on BBC Radio 4 for 'The Life Scientific' |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Interviewed by Professor Jim Al-Khalili for a BBC Radio 4 broadcast on the 'Life Scientific'. |
Year(s) Of Engagement Activity | 2019 |
Description | Lay talk at World Down Syndrome Congress |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | International |
Primary Audience | Participants in your research and patient groups |
Results and Impact | 600 people largely of either with Down syndrome or their families attended this meeting and I talked about our research and the importance of animal models for understanding Down syndrome. World Down Syndrome Congress, Cape Town, South Africa, 2012. Great enthusiasm from audience and many requests for more detailed information. Also new connections to a handful of other scientsts who were in the audience. |
Year(s) Of Engagement Activity | Pre-2006,2012 |
Description | Public talk |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Talk to memebres of the public about Down Syndrome research |
Year(s) Of Engagement Activity | 2017 |
Description | Radio and newspapers interviews over new Down syndrome article from jeanne lawrence |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Gave several interviews as an 'expert' on an important paper on Down syndrome that was published. Wider discussion of the issue. |
Year(s) Of Engagement Activity | 2013 |
Description | School Talk |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Talk to Y11-Y13 students about Down Syndrome research |
Year(s) Of Engagement Activity | 2017 |
Description | World Down Syndrome Day |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Open Day, with activities and talks, for people with Down syndrome and their friends/relations/carers. Outcome scored anonymously by attendees, positive for all scores. |
Year(s) Of Engagement Activity | 2018 |