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.
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.
Organisations
- University College London, United Kingdom (Collaboration, Lead Research Organisation)
- Catholic University of Louvain, Belgium (Collaboration)
- University of Oxford, United Kingdom (Collaboration)
- University of Edinburgh, United Kingdom (Collaboration)
- Institute of Zoology (Collaboration)
- University of Leuven (Collaboration)
- University of Ulm, Germany (Collaboration)
- Friedrich-Alexander University (Collaboration)
- Karolinska Institute, Sweden (Collaboration)
- University of California, San Francisco, United States (Collaboration)
- Cyprus Institute of Neurology and Genetics (CING) (Collaboration)
- Lausanne University, Switzerland (Collaboration)
- Medical Research Council (Collaboration)
- Helmholtz Association of German Research Centres (Collaboration)
- Children’s National Health System (Collaboration)
- Venetian Institute of Molecular Medicine (Collaboration)
- Crete University (Collaboration)
- National Institute of Health and Medical Research (INSERM) (Collaboration)
- Spanish National Research Council (CSIC) (Collaboration)
- National Center for Scientific Research (Centre National de la Recherche Scientifique CNRS) (Collaboration)
- University of Paris 6, France (Collaboration)
- University of Paris Diderot (Paris 7) (Collaboration)
- University of Stockholm (Collaboration)
- University of Nice Sophia Antipolis, France (Collaboration)
People |
ORCID iD |
| Nicoletta Kessaris (Principal Investigator) |
Publications
Amaniti EM
(2013)
Gli3 is required in Emx1+ progenitors for the development of the corpus callosum.
in Developmental biology
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
Anthwal N
(2013)
Conditional deletion of neurogenin-3 using Nkx2.1iCre results in a mouse model for the central control of feeding, activity and obesity.
in Disease models & mechanisms
Billon N
(2007)
The generation of adipocytes by the neural crest.
in Development (Cambridge, England)
Butt SJ
(2007)
Transcriptional regulation of cortical interneuron development.
in The Journal of neuroscience : the official journal of the Society for Neuroscience
Calvo CF
(2011)
Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis.
in Genes & development
Causeret F
(2011)
Dbx1-expressing cells are necessary for the survival of the mammalian anterior neural and craniofacial structures.
in PloS one
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
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 | 08/2007 |
| 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 | 03/2016 |
| End | 03/2019 |
| Description | ERC Starting Grant |
| Amount | £937,500 (GBP) |
| Organisation | European Research Council (ERC) |
| Sector | Public |
| Country | Belgium |
| Start | 05/2008 |
| 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 | Public |
| Country | United Kingdom |
| Start | 08/2007 |
| 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 | Academic/University |
| 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 | Spain |
| 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 | Academic/University |
| 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 | Academic/University |
| 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 | Spain |
| 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 | 2007,2008,2009,2010,2011,2012,2013,2014 |
| 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 |
| 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 | Regional |
| Primary Audience | Schools |
| Results and Impact | Five school-age children carried out their work placements in my lab. They were thrilled with the work. Three of them have gone on to pursue Biological degrees at University, one of them has entered Medical School and one of them entered Vet School. I receive requests for work placements every year. |
| Year(s) Of Engagement Activity | 2015,2016,2017,2018 |