Molecular genetics and development of melanocytes

Lead Research Organisation: MRC Human Genetics Unit

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

10 25 50
 
Description Chair, RSCPA Resource Sharing Working Group
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
Impact guidelines for sharing and archiving of genetically altered mice; These guidelines will be published soon. Endorsed by MRC, BBSCR, Wellcome Trust, CRUK, NC3Rs
 
Description Imperial College committee
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact Universities are improving animal care conditions
 
Description MRC Genetically Modified Mouse Welfare Assessment Group
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
Impact guidelines for rational analysis of impact of genetic modification on mouse welfare; publication of guidelines
 
Description Participation in discussions on hybrid embryos in advance of proposed Embryology Bill
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact advice to government on proposed Embryology Bill. ; Bill as finally formulated conformed with MRC's suggestions with respect to hybrid embryos
 
Description Scientific Advisory Group to PRIME (Priorities in Mouse Genomics Research in Europe)
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
Impact formulation of policy and proposals to fund mouse genetics and genomics in Europe; sustained funding from EC to mouse genetics
 
Description Transgenic mouse regulation
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact Home Office are considering changes to the regulations regarding reporting of transgenic mouse experiments
 
Description UK DNA Bank Steering Committee
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact advisory board and subsequent review of MRC UK DNA Bank; priorities and scientific direction for UK DNA Bank
 
Description Caledonian Research Foundation Fellowship
Amount £110,000 (GBP)
Organisation University of Edinburgh 
Department Caledonian Research Foundation
Sector Academic/University
Country United Kingdom
Start  
 
Description MRS Research Grant
Amount £148,872 (GBP)
Organisation Medical Research Scotland 
Sector Charity/Non Profit
Country United Kingdom
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
Start 05/2012 
End 05/2015
 
Description Responsive Mode
Amount £408,069 (GBP)
Funding ID BB/P017479/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2017 
End 09/2020
 
Title Corin 
Description mice mutant in the corin gene 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact understanding of the role of corin in regulating mammalian pigmentation 
 
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 GENA40 
Description mice with a gain of function mutation in the Gnas gene 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact understanding of the mechanisim of signalling of Mc1r 
 
Title Tyrp1 deletion 
Description sequence of the mouse genome. We played some part in the generation and analysis of the mouse genome sequence. 
Type Of Material Biological samples 
Year Produced 2006 
Provided To Others? Yes  
Impact an almost universal tool for mouse genetics 
 
Title human MC1R transgenic 
Description transgenic mice lacking their own Mc1r gene, but expressing the human MC1R 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2007 
Provided To Others? Yes  
Impact we have used this mouse line as an assay for agonists of MC1R 
 
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 Danish hair colour collaboration 
Organisation University of Copenhagen
Department Department of Forensic Medicine
Country Denmark 
Sector Academic/University 
PI Contribution genetic and phenotype data
Collaborator Contribution analysis of genetic data on hair colour associations
Impact paper published
Start Year 2007
 
Description Harwell 
Organisation MRC Harwell
Department MRC Mammalian Genetics Unit
Country United Kingdom 
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 PMID: 23902802 PMID: 24809698 PMID: 25179226 PMID: 25736793 PMID: 26542706 PMID: 27534441 PMID: 30478029 other papers pre 2006 other papers in preparation
 
Description Harwell 
Organisation MRC Harwell
Department MRC Mammalian Genetics Unit
Country United Kingdom 
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 PMID: 23902802 PMID: 24809698 PMID: 25179226 PMID: 25736793 PMID: 26542706 PMID: 27534441 PMID: 30478029 other papers pre 2006 other papers in preparation
 
Description Human hair colour genes 
Organisation University of Edinburgh
Department Department of Dermatology
Country United Kingdom 
Sector Academic/University 
PI Contribution analysis of genotypes and associations between genes and hair or eye colour
Collaborator Contribution recruitment of subjects, analysis of skin and hair phenotypes.
Impact 2 papers published
 
Description ICH: Kinsler 
Organisation University College London
Department Institute of Child Health
Country United Kingdom 
Sector Academic/University 
PI Contribution sequencing patient genes
Collaborator Contribution studying patient group
Impact publication PMID:22572819
Start Year 2010
 
Description Mc1r and pain 
Organisation University of Edinburgh
Department Centre for Neuroregeneration (CNR)
Country United Kingdom 
Sector Academic/University 
PI Contribution expertise in mouse pigmentations geneticsw
Collaborator Contribution provided expertise in analysis of pain response in mice
Impact paper published
Start Year 2007
 
Description defensins 
Organisation Medical Research Council (MRC)
Department MRC Human Genetics Unit
Country United Kingdom 
Sector Public 
PI Contribution provided expertise in coat colour genetics, and supplied mutant mice
Collaborator Contribution analysis of mouse immune phenotypes
Impact papers published
Start Year 2008
 
Description effects of agonists on Mc1r 
Organisation Galderma S.A.
Department Galderma Laboratories, L.P.
Country United States 
Sector Private 
PI Contribution confidential
Collaborator Contribution confidential
Impact this collaboration brought to us a new technique for analysing the effect of compounds on the melanocortin receptor.
 
Description mathematical modelling of cell migration 
Organisation Maxwell Institute for Mathematical Sciences
Country United Kingdom 
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 melanocyte migration: Beatson 
Organisation Beatson Institute for Cancer Research
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution supplied new technique
Collaborator Contribution input into methods for analysis
Impact Publications PMID:22109529 PMID:21924960
Start Year 2009
 
Description mouse skin and hair mutations 
Organisation MRC Harwell
Department MRC Mammalian Genetics Unit
Country United Kingdom 
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
Department Edinburgh Cancer Research UK Centre
Country United Kingdom 
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 PMID: 28869972
 
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 BBC Alba 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact interviewed for BBC Alba TV programme

NA
Year(s) Of Engagement Activity 2010
 
Description BBC Web site albinos 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact interviewed for BBC News website: debunked story on "Black Parents Give Birth to White Babies"

web hits
Year(s) Of Engagement Activity 2010
 
Description BBC web site 
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 interviewed by BBC news website about research into pain perception by red haired individuals

none known
Year(s) Of Engagement Activity 2009
 
Description British Festival of Science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact gave a talk, along with 2 others, on putting human genes into cells as part of an Academy of Medical Sciences sponsored session. Audience of about 50, mostly school and college students

press coverage of the event which was a launch of a AcadMedSci report.
Year(s) Of Engagement Activity 2010
 
Description British Festival of Science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 50-100 members of the public participated in a discussion about human:animal mosaics

interview posted on websites
Year(s) Of Engagement Activity 2010
 
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 Dublin radio show 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact was interviewed on live radio discussing research on pain perception in red haired individuals, and genetics of red hair in general

none known
Year(s) Of Engagement Activity 2009
 
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 Material World radio show 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact live radio show discussing the genetics of skin colour and cancer risk

I have had responses from general public
Year(s) Of Engagement Activity 2008
 
Description School visit: Plockton 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Emma Hall, a student in the group, was researcher in residence at Plockton High School

positive feedback from pupils and teachers
Year(s) Of Engagement Activity 2009
 
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
 
Description irish radio 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact live radio interview about "redhead day"

NA
Year(s) Of Engagement Activity 2010