Generation of neuronal diversity in the developing telencephalon

Lead Research Organisation: University College London
Department Name: The Wolfson Inst for Biomedical Research

Abstract

Our goal is to identify the stem cell origins of neurons during embryonic development.
The cerebral cortex is a specialized region of the brain where higher order functions are carried out. There are two principal neuronal cell types in the cortex: the projection neurons, which relay information from other regions of the brain, and the interneurons, which interconnect projection neurons and modify their outputs. We are far from understanding how projection neurons and interneurons form functional circuits. As a first step we need to know how many cell types there are and how their different functions are established. At least some neuronal properties are determined during development. Our work aims to determine how and where specific classes of neurons develop in the embryonic brain and whether their sites of origin determine their properties.
We will use mice as a model system in this project because we can genetically modify them and mark specific populations of neurons to allow visualization of their sites of origin and long-term fates in the adult brain.
Our work may provide clues as to whether and how abnormal interneuron development may contribute to human neurodevelopmental disorders such as epilepsy and schizophrenia where interneurons have been implicated.

Technical Summary

Understanding how the brain forms during normal embryonic development is essential not only for understanding brain function but also for gaining insight into complex neurodevelopmental disorders. The purpose of this investigation is to identify neuronal subtypes generated from neural precursors in the ventral telencephalon. I will use long-term fate-mapping tools in vivo to identify neuronal lineages and determine the extent to which their spatial and temporal origin specifies their functional properties.

Publications

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Anselmi F (2008) ATP release through connexin hemichannels and gap junction transfer of second messengers propagate Ca2+ signals across the inner ear. in Proceedings of the National Academy of Sciences of the United States of America

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Billon N (2007) The generation of adipocytes by the neural crest. in Development (Cambridge, England)

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Butt SJ (2007) Transcriptional regulation of cortical interneuron development. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Cocas LA (2011) Pax6 is required at the telencephalic pallial-subpallial boundary for the generation of neuronal diversity in the postnatal limbic system. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Costa MR (2007) The marginal zone/layer I as a novel niche for neurogenesis and gliogenesis in developing cerebral cortex. in The Journal of neuroscience : the official journal of the Society for Neuroscience

 
Description 4-year PhD project grant
Amount £113,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2007 
End 08/2011
 
Description BBSRC Response mode grant
Amount £438,000 (GBP)
Funding ID BB/N009061/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2016 
End 03/2019
 
Description ERC Starting Grant
Amount £937,500 (GBP)
Organisation European Research Council (ERC) 
Sector Public
Country European Union (EU)
Start 06/2008 
End 05/2013
 
Description Functional neuromics of the cerebral cortex.
Amount £4,189,482 (GBP)
Funding ID 108726/Z/15/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 09/2020
 
Description MRC Capacity Building Studentship
Amount £87,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2007 
End 08/2011
 
Description Project grant
Amount £497,024 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2010 
End 12/2013
 
Title Transgenic mice 
Description Transgenic mice expressing Cre recombinase in a tissue-specific manner in the embryonic brain. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2007 
Provided To Others? Yes  
Impact PMID: 19855026 PMID: 19625528 PMID: 18786357 PMID: 18487195 PMID: 17942732 PMID: 17670975 PMID: 19709629 
URL http://europepmc.org/abstract/MED/19855026
 
Description Astrocyte generation in the CNS 
Organisation University of California, San Francisco
Department School of Medicine (UCSF)
Country United States 
Sector Academic/University 
PI Contribution I provided mice for the collaboration
Collaborator Contribution They analyzed the mice for the collaborative work
Impact 22745251
Start Year 2010
 
Description Ca2+ signals across the inner ear 
Organisation Venetian Institute of Molecular Medicine
Country Italy 
Sector Academic/University 
PI Contribution We provided mice for the collaboration
Collaborator Contribution He supervised the collaborative work
Impact PMID: 19047635
Start Year 2007
 
Description Celsr3 in forebrain wiring 
Organisation Catholic University of Louvain
Country Belgium 
Sector Academic/University 
PI Contribution We provided mice for the collaborative work
Collaborator Contribution He supervised the collaborative work
Impact PMID: 18487195
Start Year 2007
 
Description Central nervous system stem cells and glia 
Organisation University College London
Department Wolfson Institute for Biomedical Research
Country United Kingdom 
Sector Academic/University 
PI Contribution I co-supervised a number of projects
Collaborator Contribution He co-supervised a number of collaborative projects and he was the PI on the MRC and Wellcome Trust grants obtained
Impact PMID: 16371946 PMID: 16388308 PMID: 17084361 PMID: 17282992 PMID: 17507398 PMID: 17670975 PMID: 18390716 PMID: 18487195 PMID: 18534921 PMID: 18849983 PMID: 19723505 PMID: 19741137 PMID: 20155815 PMID: 20569695 PMID: 21228163 PMID: 21543611
 
Description Conditional deletion of Ngn3 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Public 
PI Contribution I provided mice for the collaboration
Collaborator Contribution She supervised the collaboration
Impact 23649822
 
Description Dbx1 in forebrain neurogenesis 
Organisation Paris Diderot University
Country France 
Sector Academic/University 
PI Contribution I provided mice for the collaboration
Collaborator Contribution She supervised the collaborative work
Impact PMID:21552538
Start Year 2006
 
Description Development of the corpus callosum 
Organisation University of Lausanne
Department Department of Fundamental Neurosciences
Country Switzerland 
Sector Academic/University 
PI Contribution I provided mice for the collaboration
Collaborator Contribution She supervised the collaborative work
Impact 23420573
Start Year 2010
 
Description Functional Neuromics of the Cerebral Cortex 
Organisation Karolinska Institute
Country Sweden 
Sector Academic/University 
PI Contribution We wrote a grant application together to the Wellcome Trust. We share reagents and expertise.
Collaborator Contribution We wrote a grant application together to the Wellcome Trust. We share reagents and expertise.
Impact Wellcome TYrust Grant 108726/Z/15/Z PMID: 29912866
Start Year 2015
 
Description Functional Neuromics of the Cerebral Cortex 
Organisation Stockholm University
Country Sweden 
Sector Academic/University 
PI Contribution We wrote a grant application together to the Wellcome Trust. We share reagents and expertise.
Collaborator Contribution We wrote a grant application together to the Wellcome Trust. We share reagents and expertise.
Impact Wellcome TYrust Grant 108726/Z/15/Z PMID: 29912866
Start Year 2015
 
Description Functional Neuromics of the Cerebral Cortex 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We wrote a grant application together to the Wellcome Trust. We share reagents and expertise.
Collaborator Contribution We wrote a grant application together to the Wellcome Trust. We share reagents and expertise.
Impact Wellcome TYrust Grant 108726/Z/15/Z PMID: 29912866
Start Year 2015
 
Description Functional Neuromics of the Cerebral Cortex 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution We wrote a grant application together to the Wellcome Trust. We share reagents and expertise.
Collaborator Contribution We wrote a grant application together to the Wellcome Trust. We share reagents and expertise.
Impact Wellcome TYrust Grant 108726/Z/15/Z PMID: 29912866
Start Year 2015
 
Description Interneuron development in the telencephalon 
Organisation Spanish National Research Council (CSIC)
Country European Union (EU) 
Sector Public 
PI Contribution I provided mice for the collaborative work. I supervised part of the collaborative work
Collaborator Contribution He supervised part of the collaborative work
Impact PMID: 18786357 PMID: 19625528 PMID: 17928435
Start Year 2006
 
Description Interneuron migration to the cortex 
Organisation National Institute of Health and Medical Research (INSERM)
Department UMR-S 839 Institut du Fer à Moulin
Country France 
Sector Public 
PI Contribution I provided mice for the collaboration
Collaborator Contribution She supervised the collaborative work
Impact 23259947
Start Year 2007
 
Description Lhx proteins in telencephalic interneuron development 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Public 
PI Contribution We discuss projects and exchange reagents. I trained one lab member from the collaborative lab and members from my lab have visited the collaborative lab to learn specific techniques.
Collaborator Contribution We discuss projects and exchange reagents. We hold common group meetings.
Impact PMID: 17928435 PMID: 19855026 PMID: 21865647
 
Description Mapping adult neural stem cells in vivo 
Organisation University of California, San Francisco
Country United States 
Sector Academic/University 
PI Contribution We generated mice for fate-mapping specific populations of adult neural stem cells and we contributed to the generation of data from these mouse lines.
Collaborator Contribution They generated data using different tools
Impact PMID: 24362763
Start Year 2013
 
Description Neural crest development 
Organisation University of Zurich
Department Institute of Anatomy
Country Switzerland 
Sector Academic/University 
PI Contribution I provided mice for the collaboration
Collaborator Contribution He supervised the collaborative work
Impact 22573620
Start Year 2008
 
Description Neural crest origin of perivascular mesenchyme in the adult thymus 
Organisation University of Ulm
Country Germany 
Sector Academic/University 
PI Contribution We provided mice for the collaboration
Collaborator Contribution He supervised the collaborative work
Impact PMID: 18390716
Start Year 2006
 
Description Neurogenesis in the developing cerebral cortex 
Organisation Helmholtz Association of German Research Centres
Department Helmholtz Zentrum Munchen
Country Germany 
Sector Public 
PI Contribution We provided mice for the collaboration
Collaborator Contribution She supervised the collaborative work
Impact PMID: 17942732
Start Year 2006
 
Description Neurogenesis in the pallial-subpallial boundary 
Organisation Children’s National Health System
Department Children's Research Institute
Country United States 
Sector Academic/University 
PI Contribution We provided mice for the collaboration
Collaborator Contribution He supervised the collaborative work
Impact PMID: 21471366
Start Year 2007
 
Description Optogenetic control of cortical interneurons 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution We will generate a transgenic mouse for the collaboration
Impact NA
Start Year 2009
 
Description Role of Rac1 in neurogenesis 
Organisation University of Crete
Department Division of Basic Sciences
Country Greece 
Sector Academic/University 
PI Contribution I trained one lab member from the collaborative lab
Collaborator Contribution She supervised part of the collaborative work
Impact PMID:21690261
Start Year 2006
 
Description Schwann cell development 
Organisation Spanish National Research Council (CSIC)
Country European Union (EU) 
Sector Public 
PI Contribution I supervised the generation of a new transgenic mouse and trained the group leader in this technology
Collaborator Contribution He carried out and supervised part of the collaboration
Impact PMID: 19741137
Start Year 2007
 
Description Sox proteins in oligodendrocytes 
Organisation Friedrich-Alexander University Erlangen-Nuremberg
Country Germany 
Sector Academic/University 
PI Contribution We provided mice for the collaborative work
Collaborator Contribution He supervised the collaborative work
Impact PMID: 17084361
 
Description Spinal cord development 
Organisation Cyprus Institute of Neurology and Genetics (CING)
Country Cyprus 
Sector Academic/University 
PI Contribution I provided advice, training and supervision for some of the work
Collaborator Contribution He supervised some of the work
Impact PMID: 19723505 PMID: 20844123 PMID: 23816521
 
Description The generation of adipocytes by the neural crest 
Organisation University of Nice Sophia-Antipolis
Country France 
Sector Academic/University 
PI Contribution We provided mice for the collaboration
Collaborator Contribution She carried out much of the collaborative work
Impact PMID: 17507398
 
Description The role of Gli3 in the development of the corpus callosum 
Organisation University of Edinburgh
Department Centre for Integrative Physiology
Country United Kingdom 
Sector Academic/University 
PI Contribution I provided mice for the collaboration
Collaborator Contribution He supervised the work
Impact 23396189
Start Year 2010
 
Description The role of Sip1 in interneuron migration 
Organisation University of Leuven
Department Department of Development and Regeneration
Country Belgium 
Sector Academic/University 
PI Contribution I provided mice for the collaboration
Collaborator Contribution She supervised the collaborative work
Impact 23312517
Start Year 2007
 
Description VEGFR3 in neurogenesis 
Organisation Pierre and Marie Curie University - Paris 6
Department The Institute of Brain and Spinal Cord Injury (MHI)
Country France 
Sector Academic/University 
PI Contribution I trained one lab member in the collaborative lab
Collaborator Contribution He supervised the collaborative work
Impact PMID:21498572
Start Year 2008
 
Description nNOS interneurons in the cortex 
Organisation National Center for Scientific Research (Centre National de la Recherche Scientifique CNRS)
Department Laboratory for Brain Plasticity
Country France 
Sector Public 
PI Contribution I provided material for the collaboration
Collaborator Contribution She analyzed the material
Impact 22754499
Start Year 2010
 
Description Set up of a web site describing the ongoing work in the lab 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The web site is designed both for academic and non-academic audiences alike.

None that I am aware of.
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011
URL http://www.homepages.ucl.ac.uk/~rmgzntk/
 
Description Work placement for school children 
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 Schools
Results and Impact The students were thrilled to be able to experience research first-hand. One of the students came back for more work experience and has decided to combine research with his future Vet studies.

I have been invited to their school to talk about my research and inform the students.
Year(s) Of Engagement Activity 2014