The role of N-cadherin in neural stem cells

Lead Research Organisation: University of Edinburgh
Department Name: MRC Centre for Regenerative Medicine

Abstract

Like all tissues, the brain grows from a small population of stem cells - cells with the ability to divide indefinitely and generate all the cell types in a given tissue. To do this, stem cells first divide symmetrically, increasing their numbers, and then asymmetrically to generate a daughter cell that goes on to form a brain cell and also a new stem cell. Over the past few years, molecular cues involved in the control of these stem cell divisions have been identified in invertebrate model systems, especially Drosophila and C. elegans. Despite this, the mechanisms controlling symmetric and asymmetric divisions, and the switch between them, remain poorly understood in the vertebrate brain. They are, however, an important cause of neurodevelopmental diseases such as microcephaly that result from an inadequate expansion of the neural stem cell pool. A number of different studies suggest the hypothesis that the molecules that stick cells together - cadherins - found in special structures called adherens junctions (AJ) play a major role. The aim of this project is to test this hypothesis, so identifying novel mechanisms in the development of the mammalian brain and potentially suggesting strategies for the manipulation of neural stem cells so as to promote repair.

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.

Planned Impact

Beneficiaries of the research will be

i) patients with diseases of the CNS in whom enhancing stem cell activity might promote repair. In diseases such as stroke and MS, increasing the activity of stem cells present in the adult CNS represents a strategy to increase the number of new cells available for repair. Our work investigating the mechanisms by which stem cells generate new cells could lead to the development of new therapies to enhance stem cell activity following injury and so provide treatments for diseases based on repairing the damage rather than simply preventing further injury.

ii) Biotech and Pharma companies looking for novel strategies to promote stem cell mediated repair in the CNS. Our work could both help develop models for the validation and screening of potential therapies, and also provide new targets for drug development. There are currently no regenerative therapies in the clinic, and knowledge such as that to be gained from our study will be essential if these treatments are to be developed. As degenerative diseases of the CNS cause enormous societal costs - MS alone costs the EU 9 billion Euros annually - the potential impact of these treatments is large.
 
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,a nd 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 advisory committee
 
Description post doc fellowship
Amount € 70,000 (EUR)
Organisation German Research Foundation 
Sector Public
Country Germany
Start 10/2017 
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