Stem and progenitor cells of the postnatal CNS

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

Abstract

One of the big surprises in neurobiology recently has been the realization that there are pockets of stem cells in the adult brain that continuously generate new neurons throughout life, both in rodents and humans. The majority of ?adult-born? neurons populate the olfactory bulb (a brain structure required for recognition and memory of odors) and the hippocampus (an enigmatic structure involved in laying down memories of places and events). We are still in the dark about the precise role of the new neurons. Nevertheless, there is widespread excitement that, because stem cells can generate some types of neurons under normal conditions, they might have a wider potential to generate neurons to replace those that are lost through injury or neurodegenerative diseases like Parkinson?s or Alzheimer?s. This is a challenging idea because, as far as we know, the stem cells do not normally make the kinds of neurons that are destroyed in these diseases. The question is, do they have the potential to make the neurons we want, if only we could learn how to ?tweak? them?

We and others recently discovered that there is not just one kind of stem cell in the healthy brain but several, possibly many, that have slightly different properties and that specialize in making different kinds of neurons in the olfactory bulb. This is encouraging because it implies that there might be yet more types of stem cells that we don?t know about yet, perhaps some with the properties we are looking for. On the other hand, it complicates the picture because we now have more cells to sort through. In the programme of work we describe here we make a start towards understanding the different behaviours we might expect from different stem cell subtypes when they are confronted with different forms of damage such as ischemia (interruption of blood supply such as occurs during stroke) or demyelination (loss of the insulating layer around nerve fibres, such as happens in multiple sclerosis) or in a genetic form of motor neuron disease (in which spinal motor neurons die, leading to paralysis. We will do this by genetically manipulating mice to mark one stem cell subtype or the other with a fluorescent label, so that we can follow their behaviour separately in the intact brain. The fluorescent label also allows us to purify and study them separately in a culture dish.

Technical Summary

We showed recently that the adult forebrain subventricular zone (SVZ) contains a mixture of stem cells that have spatially diverse origins in the embryonic telencephalon and different neurogenic properties in the adult. We shall use genetically manipulated mice to dissect the roles of these different SVZ stem cell sub-populations in adult olfactory neurogenesis and olfactory behaviour, and their possibly distinct regenerative responses to damage. There are also stem cells in the adult spinal cord ependymal zone (EZ) surrounding the central canal. By analogy with the SVZ, the EZ might be expected to inherit the spatially patterned cell fate restrictions of the embryonic neuroepithelium. We will test this by mapping the embryonic origins of the EZ and asking whether embryonic ancestry predicts adult stem cell response to degenerative disease (a genetic model of motor neuron disease), demyelination or physical injury. Finally, we shall examine the role of ?NG2 cells? ? an abundant and ubiquitous population of progenitor cells in the adult CNS ? in adult gliogenesis and cortical neurogenesis, testing the ideas that de novo myelination of previously naked axons contributes to neural plasticity and that adult-born cortical projection neurons likewise have a significant functional role.

Publications

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Clarke LE (2012) Properties and fate of oligodendrocyte progenitor cells in the corpus callosum, motor cortex, and piriform cortex of the mouse. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Espinosa-Medina I (2016) The sacral autonomic outflow is sympathetic. in Science (New York, N.Y.)

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Gomez-Sanchez JA (2009) Sustained axon-glial signaling induces Schwann cell hyperproliferation, Remak bundle myelination, and tumorigenesis. in The Journal of neuroscience : the official journal of the Society for Neuroscience

 
Description SAB Institute for Brain and Spinal Cord (ICM), Paris
Geographic Reach Europe 
Policy Influence Type Participation in advisory committee
 
Description ERC Advanced Grant (MOTOGLIA: axoglial synapses, adult myelination and motor skills learning)
Amount £1,857,744 (GBP)
Funding ID 293544 
Organisation European Research Council (ERC) 
Sector Public
Country Belgium
Start 02/2012 
End 01/2017
 
Description NIH RO1
Amount $700,000 (USD)
Funding ID RO1NS059893 
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start  
 
Description Wellcome Prize Studentship
Amount £31,882 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Wellcome Prize Studentship
Amount £28,298 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Wellcome Trust Senior Investigator Award
Amount £1,900,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2013 
End 02/2018
 
Title Olig2 phospho-S147 
Description A rabbit antiserum raised against a specific phospho-peptide of the transcription factor Olig2. It recognizes the phosphorylated form of Olig2(Serine147), a predicted protein kinase A target, on Western blots. 
Type Of Material Antibody 
Year Produced 2011 
Provided To Others? Yes  
Impact Too early to say. 
 
Title confocal microscope 
Description this programme grant allowed the purchase of a confocal microscope that is used by several groups at UCL as well as our own 
Type Of Material Improvements to research infrastructure 
Year Produced 2009 
Provided To Others? Yes  
Impact publications in preparation or submitted 
 
Title genetically manipulated mice 
Description multiple lines of mice expressing Cre recombinase under transcriptional control of genes that are important for stem/precursor cell development and function 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2006 
Provided To Others? Yes  
Impact Collaborative publications, non-collaborative publications. Our mice have been distributed to more than 100 labs world-wide for a wide range of studies on diverse subjects including central and peripheral nervous systems, immune system, adipose (fat) tissue, the inner ear, early embryos, demyelinating disease, Alzheimers disease, motor neuron disease, spinal injury etc etc 
 
Description Control of myelination by lactate and glucose 
Organisation University College London
Department Neuroscience, Physiology & Pharmacology
Country United Kingdom 
Sector Academic/University 
PI Contribution We generated and maintained a transgenic mouse line that was central to this research and provided input to the interpretation of results
Impact Published paper in Journal of Neuroscience 2010
Start Year 2009
 
Description Control of neural stem cell development by vascular factors 
Organisation Yale University
Department Cardiovascular Medicine
Country United States 
Sector Academic/University 
PI Contribution We hosted a visitor from collaborating lab to instruct her in BAC transgenesis, resulting in the successful generation of a mouse line that was central to the collaborative research
Impact Research paper in Genes & Development, 2011
Start Year 2009
 
Description Development and function of astrocytes 
Organisation Howard Hughes Medical Institute
Country United States 
Sector Charity/Non Profit 
PI Contribution We "recombineered" bacterial artificial chromosome transgenes designed to mark astrocytes with a fluorescent protein, or to kill astrocytes by expression of diphtheria toxin, in order to study the development and functional roles of astrocytes
Collaborator Contribution Our partners used our transgenes to generate transgenic mice which were analyzed further by ourselves and our partners
Impact 1. A high-profile publication in the journal Science 2. Transgenic mouse lines for neuroscience research
Start Year 2008
 
Description Oligodendrocytes in amyotrophic lateral sclerosis (motor neuron disease) 
Organisation University of Leuven
Department VIB Vesalius Research Center
Country Belgium 
Sector Academic/University 
PI Contribution We provided transgenic mice, advice and helped write the paper
Collaborator Contribution They did most of the analysis
Impact Joint publication in the journal Brain
Start Year 2007
 
Description Remyelination by NG2 cells 
Organisation University of Cambridge
Department Department of Veterinary Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We made the transgenic mice central to this work, maintained the mice, helped analyze the experiments and helped write the paper
Collaborator Contribution It has resulted in a grant application (recently funded) to the Wellcome Trust for a Veterinary Clinical Training Fellowship for collaborative research between our lab and that of Robin Franklin
Impact Publication Zawadzka et al. in Cell Stem Cell 2010
Start Year 2008
 
Description Role of Neuregulin 1 in peripheral myelination 
Organisation Miguel Hernández University of Elche (UMH)
Department Neurosciences Institute UMH
Country Spain 
Sector Academic/University 
PI Contribution Hosted the collaborator in our lab, taught him BAC recombineering and transgenesis, successfully made transgenic line that was central to the collaboration
Impact Publication, Cabedo et al., in Journal of Neuroscience 2009
Start Year 2008
 
Description Transcriptional control of oligodendrocyte development 
Organisation Friedrich-Alexander University Erlangen-Nuremberg
Country Germany 
Sector Academic/University 
PI Contribution we provided transgenic mice
Collaborator Contribution joint publication
Impact 17084361
Start Year 2006
 
Description development of adipocytes 
Organisation College of France
Country France 
Sector Academic/University 
PI Contribution we provided transgenic mice
Collaborator Contribution they performed the analysis
Impact collaborative publication
Start Year 2006
 
Description forebrain wiring 
Organisation Catholic University of Louvain
Country Belgium 
Sector Academic/University 
PI Contribution we provided transgenic mice
Collaborator Contribution collaborative publication
Impact 18487195
Start Year 2006
 
Description neural stem cells 
Organisation Helmholtz Association of German Research Centres
Department Helmholtz Zentrum Munchen
Country Germany 
Sector Academic/University 
PI Contribution we provided transgenic mice
Collaborator Contribution collaborative publication
Impact 17942732
Start Year 2006
 
Description pituitary development 
Organisation Marie Curie
Department Marie Curie Research Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution we hosted a visiting researcher from the collaborator's lab
Collaborator Contribution collaborative publication
Impact 18534921
Start Year 2006
 
Description thymus development 
Organisation University of Ulm
Country Germany 
Sector Academic/University 
PI Contribution we provided transgenic mice
Collaborator Contribution Collaborative publication
Impact 18390716
Start Year 2006
 
Description Presentation of our research using transgenic mice to Lynne Featherstone, MP and Home Office Minister 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Policymakers/politicians
Results and Impact I subsequently received a hand-written letter of thanks and appreciation from Lynne Featherstone stating " My knowledge and understanding were genuinely broadened by our encounter" and "Absolutely and reassuringly impressed with the condition of laboratories and the important work being done."

Too early to say. However, it is crucially important to reassure the Home Office of the worth of animal research and I believe my presentation and conversation with the MP helped to achieve this.
Year(s) Of Engagement Activity 2011
 
Description media engagement 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Online and in-print summary articles of our Science 2014 paper appeared in The Mail Online, MS Discovery Forum, The Scientist, The Telegraph, BrainFacts.org

The Mail Online article was "shared" 80+ times on social media
Year(s) Of Engagement Activity 2014
URL http://www.dailymail.co.uk/sciencetech/article-2795922/your-musical-talents-determined-fatty-substan...