The role of N-cadherin in neural stem cells
Lead Research Organisation:
University of Edinburgh
Department Name: MRC Centre for Regenerative Medicine
Abstract
The human brain develops from a pool of special cells called neural stem cells. These cells divide throughout life, generating the new nerve cells required for the growth of the brain during development and for its maintenance in adult life. At the same time, the stem cells are not depleted, and this is achieved by a process called 'asymmetrical division', where the two cells formed by a dividing stem cell (daughter cells) have different fates / one becomes a nerve cell while the other remains a stem cell so renewing the stem cell population. Clearly, then, the mechanisms that enable these asymmetrical divisions are absolutely fundamental to the correct development of the brain, and we know that abnormalities cause mental retardation syndromes in children. We also know that the difference in cell fates is achieved by two mechanisms; first, the precise location to one part of the cell of special molecules that control fate ('fate determinants') and second, control of exactly where the cell splits apart during division so that these fate determinants all end up in only one of the two daughter cells. We don't know, however, the details of these two mechanisms and how they so precisely locate fate determinants and cell splitting. Here, we will ask whether a group of molecules called cadherins, known to stick the neural stem cells together on the outside so keeping them in the correct place in the developing brain, also bind to the fate determinants and cell-splitting molecules on the inside and keep them in the right place. We will do this by using molecular biology to alter the location of cadherins on the neural stem cells, using slices of rat brain to model the human brain and enable these experiments do be done in tissue culture. We will then see what happens to the dividing neural stem cells and so prove or disprove our ideas as the function of these cadherins. As stem cells throughout the body use quite similar mechanisms to divide, our results will be valuable not only for a better understanding of the brain but also for other tissues where stem cells might provide a means of repair following disease.
Technical Summary
The mammalian central nervous system (CNS) develops from neural stem cells (NSC) that initially undergo symmetric divisions, expanding the stem cell pool before initiating asymmetric divisions that generate a committed neuronal precursor cell as well as another NSC. Based largely on studies in invertebrates, the key factors enabling symmetrical and asymmetrical division in vertebrate NSC are known to be the localization of fate determinants to the apical region of the cell and precise regulation of the plane of cleavage. At present we have an incomplete understanding of how these are achieved and in particular how they are orientated appropriately for the 3D environment of the developing CNS. A number of different studies suggest the hypothesis that cadherins in adherens junctions (AJ) play a major role by anchoring the astral microtubules that define the position of the centrosome and/or binding fate determinants, in addition to their adhesive role in maintaining the apical pole of the NSC within the ventricular zone. This extended role of cadherins in the regulation of NSC has not previously been examined directly, and the aim of this project is therefore to test this hypothesis. To do this, we will use slice cultures of embryonic CNS to determine the effect on NSC of disrupting or mislocalizing N-cadherin. Using confocal microscopy, we will examine the consequent changes in both division axis and the location of fate determinants, as well as in the fate of the daughter cells. The results will identify novel mechanisms in the development of the mammalian CNS and may suggest strategies for the manipulation of neural stem cells so as to promote repair.
People |
ORCID iD |
Charles Ffrench-Constant (Principal Investigator) |
Publications
Pouwels PJ
(2014)
Hypomyelinating leukodystrophies: translational research progress and prospects.
in Annals of neurology
Megaw R
(2017)
Gelsolin dysfunction causes photoreceptor loss in induced pluripotent cell and animal retinitis pigmentosa models.
in Nature communications
Mayerl S
(2020)
Hippocampal Neurogenesis Requires Cell-Autonomous Thyroid Hormone Signaling.
in Stem cell reports
Long KR
(2014)
Neural stem cell quiescence comes to an un-sticky end.
in Nature cell biology
Long K
(2016)
Integrin signalling regulates the expansion of neuroepithelial progenitors and neurogenesis via Wnt7a and Decorin.
in Nature communications
Licht T
(2016)
VEGF preconditioning leads to stem cell remodeling and attenuates age-related decay of adult hippocampal neurogenesis.
in Proceedings of the National Academy of Sciences of the United States of America
Gyllborg D
(2018)
The Matricellular Protein R-Spondin 2 Promotes Midbrain Dopaminergic Neurogenesis and Differentiation.
in Stem cell reports
Chandran JS
(2014)
Disc1 variation leads to specific alterations in adult neurogenesis.
in PloS one
Ahmed M
(2021)
Combinatorial ECM Arrays Identify Cooperative Roles for Matricellular Proteins in Enhancing the Generation of TH+ Neurons From Human Pluripotent Cells.
in Frontiers in cell and developmental biology
Ahmed M
(2016)
Extracellular Matrix Regulation of Stem Cell Behavior.
in Current stem cell reports
Description | Role of extracellular matrix in neural development |
Exploitation Route | By using matrix to drive neuron formation in vitro for the generation of cells for drug screening. We have now confirmed this using a custom ECM array, showing that we can enhance the generation of human dopaminergic nerons from ES cells by a combination of three matricellular proteins, and this is being prepared for publication |
Sectors | Pharmaceuticals and Medical Biotechnology |
Description | BIRAX |
Geographic Reach | Europe |
Policy Influence Type | Membership of a guideline committee |
Description | Bristol review |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | post doc fellowship |
Amount | € 70,000 (EUR) |
Organisation | German Research Foundation |
Sector | Charity/Non Profit |
Country | Germany |
Start | 09/2017 |
End | 10/2019 |
Description | BIRAX grant |
Organisation | Hebrew University of Jerusalem |
Country | Israel |
Sector | Academic/University |
PI Contribution | expertise in stem cell biology |
Collaborator Contribution | expertise in vascular biology |
Impact | Grant from BIRAX |
Start Year | 2013 |
Description | CffC/Karolinska |
Organisation | Karolinska Institute |
Country | Sweden |
Sector | Academic/University |
PI Contribution | Expertise in neural stem cell biology and extracellular matrix |
Collaborator Contribution | Generation of RNAseq datasets |
Impact | List of ECM genes expressed in develiping CNS |
Start Year | 2015 |
Description | Disc1 |
Organisation | University of Edinburgh |
Department | School of Molecular Medicine Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Expertise in neurogenesis |
Collaborator Contribution | Expertise in schizophrenia |
Impact | Paper |
Start Year | 2010 |
Description | yale |
Organisation | Yale University |
Department | School of Medicine |
Country | United States |
Sector | Academic/University |
PI Contribution | Expertise in stem cell biology and extracellular matrix |
Collaborator Contribution | expertise in vascular biology and stroke models |
Impact | Grant from NIH |
Start Year | 2014 |
Description | Cheltenham Science festival |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Questions afterwards none |
Year(s) Of Engagement Activity | 2014 |