Molecular genetics and development of melanocytes

Lead Research Organisation: University of Edinburgh

Abstract

The cells that produce the pigment in hair and skin, melanocytes, develop from cells in the embryo that also produce cells of the nervous system. Understanding how these very different cell types come from a single precursor is an important question in developmental biology. As this is a fairly simple developmental process and one that can be studied in culture, rather than in live embryos, it acts as a model for the understanding of more complex events. We are investigating what molecules direct this process, by blocking the action of specific genes and by examining mouse embryos in which genes have been mutated.

The amount and type of pigment that melanocytes make is controlled by a protein on the cell surface. Individuals in whom this protein is less active usually have red hair and skin that burns easily in the sun. We are studying human populations to identify other molecules that interact in this process to affect sun sensitivity. We are also looking at other functions for this protein; it has been suggested that it is involved in feeling pain and the effectiveness of pain killers or anaesthetics.

Technical Summary

Melanocytes differentiate and migrate from the neural crest during mammalian development. We are able to culture neural tubes from early mouse embryos and skin from later embryos and melanoblasts proliferate and migrate within the cultures. We have developed a live-imaging system which allows us to observe migrating cells within the skin and their localisation to the hair follicles. We can manipulate the system with drugs which inhibit receptors, kinases etc investigate the pathways controlling the migration, or can use cultures derived from mutant mice to see the effect of loss of other genes.

The MSH receptor, MC1R, controls the type of melanin made by the melanocyte. Variants in the protein are common in the Caucasian population and two variant alleles usually results in red hair and pale skin. Other genes modify the effect of MC1R variants and we are undertaking a study to assess what role is played by variation in candidate modifiers. Mouse and human MC1R are different in the strength of their signalling, and their dependence on ligand binding. We have analysed mice in which we have replaced the mouse receptor with the human one and demonstrated differences in signalling between the two. We are interested in the mechanism by which agouti signalling protein, ASP, modulates signalling at MC1R.

We have identified two novel mouse mutations that affect the signalling through MC1R and have identified the genes affected in both cases. These are providing insight into the mechanism of signalling downstream of MC1R, and the regulation of the ASP/MC1R interaction.

MC1R has been suggested to be involved in pain response and analgesia and in inflammatory responses. We have investigated this role using transgenic and mutant mice. We find that female mice mutant for MC1R have a reduced sensitivity to noxious heat, but an enhanced sensitivity to noxious cold. Males however are unaffected. The hyperalgesic and allodynic effects of inflammation are also enhanced in the mutants.

Publications


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Glover JD (2015) Maintenance of distinct melanocyte populations in the interfollicular epidermis. in Pigment cell & melanoma research
Jackson I (2011) Evolution in action: highlighting a role for the Agouti gene in development? in Pigment cell & melanoma research
Mort RL (2015) The melanocyte lineage in development and disease. in Development (Cambridge, England)
 
Description Imperial College committee
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact Universities are improving animal care conditions
 
Description Infrafrontier advisory
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
 
Description NC3Rs Board
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact National Centre for 3Rs influences academia, government and industry in their use of animals in research
 
Description MRS Research Grant
Amount £148,872 (GBP)
Organisation Medical Research Scotland 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2011 
End 10/2014
 
Description NC3Rs Studentship
Amount £90,000 (GBP)
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Private
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 05/2012 
End 05/2015
 
Description Pilot Project Grant
Amount £44,848 (GBP)
Funding ID NC/M001091/1 
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Private
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 02/2015 
End 11/2015
 
Title FUCCI2a 
Description An improved method for visualising cell cycle in vivo 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2014 
Provided To Others? Yes  
Impact publication in press 
 
Title live imaging system 
Description method for live imaging of melanoblasts migrating in embryonic skin 
Type Of Material Technology assay or reagent 
Year Produced 2010 
Provided To Others? Yes  
Impact paper published, collaborations established 
 
Description CGAT 
Organisation University of Oxford
Department Department of Physiology, Anatomy and Genetics
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution supervision of postdoc, analysis of data
Collaborator Contribution analysis of data
Impact studentship awarded to continue analysis
Start Year 2015
 
Description Harwell 
Organisation Medical Research Council (MRC)
Department MRC Mammalian Genetics Unit
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution We take the mice, map and identify the genes affected and analyse the phenotype
Collaborator Contribution screening of mice for chemically induced mutant eye phenotypesidentification of mutant mouse strains, and generation of mutant mouse models
Impact PMID: 20943750 PMID: 20056676 PMID: 18765564 PMID: 16825286 PMID: 24809698 PMID: 23902802 PMID: 23633653 other papers pre 2006 other papers in preparation
 
Description Harwell 
Organisation Medical Research Council (MRC)
Department MRC Mammalian Genetics Unit
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution We take the mice, map and identify the genes affected and analyse the phenotype
Collaborator Contribution screening of mice for chemically induced mutant eye phenotypesidentification of mutant mouse strains, and generation of mutant mouse models
Impact PMID: 20943750 PMID: 20056676 PMID: 18765564 PMID: 16825286 PMID: 24809698 PMID: 23902802 PMID: 23633653 other papers pre 2006 other papers in preparation
 
Description Headon 
Organisation University of Edinburgh
Department The Roslin Institute
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution collaboration on idenfication of melanocyte stem cell in skin
Collaborator Contribution provision of transgenic mice analysis of data
Impact publication PMID:25847135
Start Year 2014
 
Description ICH: Kinsler 
Organisation University College London (UCL)
Department Institute of Child Health
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution sequencing patient genes
Collaborator Contribution studying patient group
Impact publication PMID:22572819
Start Year 2010
 
Description Stamford 
Organisation Stanford University
Country United States of America 
Sector Academic/University 
PI Contribution tested potential MC1R agonists in a transgenic mouose model
Collaborator Contribution identified potential agonists
Impact results were negative
Start Year 2014
 
Description Weiner: pig genomics 
Organisation University of Edinburgh
Department The Roslin Institute
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution analysis of pig genomic data
Collaborator Contribution generation and analysis of pig genomic data
Impact publication PMID:23637623
Start Year 2012
 
Description Yates maths 
Organisation University of Bath
Department Department of Mathematical Sciences
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution provided biological data
Collaborator Contribution produced mathematical models
Impact publication PMID:26732977 multidisciplinary: mathematics and developmental biology
Start Year 2012
 
Description mathematical modelling of cell migration 
Organisation Heriot-Watt University
Department Maxwell Institute for Mathematical Sciences
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution generating data for input into models and testing mathematical models experimentally
Collaborator Contribution input of mathematics expertise
Impact award of grant Multidisciplinary: mathematics and developmental biology
Start Year 2010
 
Description mouse skin and hair mutations 
Organisation Medical Research Council (MRC)
Department MRC Mammalian Genetics Unit
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution identification and characterisation of mutant genes affecting hair development
Collaborator Contribution identification and supply of mutant mice with skin and hair defects
Impact Impact has been "this collaboration has meant we have begun working on a number of interesting mouse mutations which inform us about the developmental processes involved in hair and pigment formation. We have made significant progress in a number of areas"
 
Description zebra fish 
Organisation Cancer Research UK (CRUK)
Department Edinburgh Cancer Research UK Centre
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution expertise in mouse pigmentation genetics
Collaborator Contribution expertise in analysis of zebrafish pgmentation phenotypes
Impact papers published PMID:21771814 PMID:23831555 PMID:25670789
 
Title MC1R transgenic mice 
Description Mice lacking their own Mc1r gene, but containing the human equivalent 
IP Reference  
Protection Protection not required
Year Protection Granted
Licensed Yes
Impact analysis of differences between human and mouse Mc1r signalling
 
Description Cafe Scientifique edinburgh 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact 30 members of the public discussing genetics of red hair

interst in the field
Year(s) Of Engagement Activity 2013
 
Description Cafe Scientifique glasgow 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact talk and discussion about the genetics of red hair

interest in field
Year(s) Of Engagement Activity 2013
 
Description Cafe Scientifique: Cockermouth 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact talk on red hair genetics to general public
Year(s) Of Engagement Activity 2015
 
Description Debating Matters 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact discussion on scientific and non-scientific topics

invitation to participate again
Year(s) Of Engagement Activity 2012
 
Description Edinburgh Festival Fringe 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact discussed genetics of red hair with 25 paying members of the public from around the world

interest in the topic
Year(s) Of Engagement Activity 2013
 
Description HO Press briefing 2013 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact part of panel media briefing on Home Office statistics on use of animals for 2012

newspaper and website coverage
Year(s) Of Engagement Activity 2013
 
Description NC3Rs prize reception 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact reception associated with NC3Rs prize award
Year(s) Of Engagement Activity 2015,2016,2017
 
Description animal transport interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact interview for BBC Radio 4 about the impact of the ban by ferry companies on carrying research animals

press awareness
Year(s) Of Engagement Activity 2012
 
Description black and white 
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 Public/other audiences
Results and Impact press release on our Nature Communications paper. It was picked up by many newspapers in the UK and internationally.
Year(s) Of Engagement Activity 2016
URL http://www.hgu.mrc.ac.uk/news_section/news_1.2016.html