Cilia Development & Disease

Lead Research Organisation: MRC Mammalian Genetics Unit

Abstract

Cilia are hair-like extensions from the cell surface. Most will have heard of the specialised motile cilia functioning in the trachea, beating to bring mucus up from the lungs; these cilia stop beating in response to the flu or smoking, leading to coughing. Similar motile cilia function in the brain and the reproductive tract; during development cilia are required to establish a proper left and right hand side. Other cells have a single non-motile cilium. These have been implicated in cell-cell signalling, stress perception, hearing, vision and appetite, leading their description as the cellular antenna.
Defective cilia are known to result in a broad range of diseases including Primary Ciliary Dyskinesia (PCD), Polycystic Kidney Disease (PKD), Bardet Biedl Syndrome (BBS), Meckel Syndrome (MKS) and Orofaciodigital Syndrome (OFD). While distinct, these disorders result in overlapping defects; together have become known as the ciliopathies and they represent a significant burden of genetic disease.
We are interested in the role of cilia in mammalian disease and development. Using genetics, cell biological and biochemical approaches we are studying ciliogenesis, left-right patterning and cilia related disease. The aim of this programme is to understand the normal function of cilia, the effects of defective cilia and to develop models of human disease (ciliopathies) with the ultimate goal of identifying and developing therapeutic strategies.

Technical Summary

Cilia are microtubule based extensions of the centriole that are present in almost every cells of the body. Specialised motile cilia function in the trachea, ependyma of the brain and the reproductive tract; during development cilia are also required for establishing left-right patterning. In contrast, most cells have a single non-motile primary cilium. Primary cilia have been implicated in cell-cell signalling (particularly the hedgehog pathway), planar cell polarity, stress perception, hearing, vision and obesity leading some to describe them as the cellular antenna.
Defective cilia are known to result in a broad range of diseases including Primary Ciliary Dyskinesia (PCD), Polycystic Kidney Disease (PKD), Bardet Biedl Syndrome (BBS), Meckel Syndrome (MKS) and Orofaciodigital Syndrome (OFD). While individual and distinct, these disorders result in a range of overlapping defects and together have become known as the ciliopathies.
We are interested in the role of cilia in mammalian disease and development. Using mouse genetics, cell biological and biochemical approaches we are studying ciliogenesis, left-right patterning and cilia related disease. The aim of this programme is to understand the normal function of cilia, the effects of defective cilial function and to develop mouse models of human ciliopathies with the ultimate goal of identifying and developing therapeutic strategies.
Current work concentrates on mechanisms by which cilia generate flow and the role of cilia in flow detection. This is of particular relevance to PCD, PKD and to left-right patterning. Our other major area of research is characterising the genetic control of the process of ciliogenesis and has resulted in the identification of a novel transcriptional regulator and a major target of this regulation.

Publications

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Chen D (2014) Chemosignalling, mechanotransduction and ciliary behaviour in the embryonic node: Computational evaluation of competing theories. in Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine

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Cole JM (2018) High-resolution ┬ÁCT of a mouse embryo using a compact laser-driven X-ray betatron source. in Proceedings of the National Academy of Sciences of the United States of America

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Ermakov A (2009) Mouse mutagenesis identifies novel roles for left-right patterning genes in pulmonary, craniofacial, ocular, and limb development. in Developmental dynamics : an official publication of the American Association of Anatomists

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Field S (2011) Pkd1l1 establishes left-right asymmetry and physically interacts with Pkd2. in Development (Cambridge, England)

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Goggolidou P (2014) ATMIN is a transcriptional regulator of both lung morphogenesis and ciliogenesis. in Development (Cambridge, England)

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Goggolidou P (2013) A chronological expression profile of gene activity during embryonic mouse brain development. in Mammalian genome : official journal of the International Mammalian Genome Society

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Goggolidou P (2014) Atmin mediates kidney morphogenesis by modulating Wnt signaling. in Human molecular genetics

 
Description Ciliopathy Alliance Scientific and Clinical Advisory Board
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
URL http://www.ciliopathyalliance.org
 
Description Participation in BEAT-PCD COST action
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
URL https://beat-pcd.squarespace.com/
 
Title Rikishi 
Description A model of heterotaxia 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2013 
Provided To Others? Yes  
Impact n/a 
 
Description CLF imaging 
Organisation Rutherford Appleton Laboratory
Department Central Laser Facility
Country United Kingdom 
Sector Public 
PI Contribution We have provided samples for imaging work. We have provided discussion on the nature the kinds of imaging that are important for biology/medicine We have provided some analysis of results
Collaborator Contribution Establishment of a new modality of 3D imaging Development of the imaging modality Running the actual imaging
Impact A first run has been performed. A second set of experiments (requiring dedicated time on the peta-watt lasers) is scheduled for 2015 - a 2 week session of laser time has been assigned to our collaborators.
Start Year 2012
 
Description Cardiac Phenotyping 
Organisation University of Oxford
Department Wellcome Trust Centre for Human Genetics
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual and practical input- we provided genetics and embryological expertise, they cardiac expertise.
Collaborator Contribution Expertise in cardiac phenotyping and access to MRI scanning of mutants
Impact Publication 19235720 They have identified a new allele of a gene involved in cardiac patterning/function- a reagent available to the community.
Start Year 2006
 
Description Danish cilia lab 
Organisation University of Copenhagen
Country Denmark 
Sector Academic/University 
PI Contribution We have driven the main research effort, defining a novel set of gene required for cilia function
Collaborator Contribution Production of novel DNA constructs analysis of aspects of cell biology intellectual input into aspects of the project
Impact Academic publication, Goggolidou et al, 2014 Sharing of reagents between research groups. Reagents that we have created are in use by the Denmark group.
Start Year 2013
 
Description Flow chamber analysis 
Organisation University of Toledo
Department Department of Pharmacology
Country United States 
Sector Academic/University 
PI Contribution We have been performing research and wanted help with one experiment. So I suppose you would say that we have performed >90% of the work, we have planned the work and we have driven the conceptual basis of the work.
Collaborator Contribution They have performed specialised experiments in a flow chamber, analysing our reagents and providing data for a publication.
Impact We have data for a paper that we are about to submit.
Start Year 2013
 
Description Mechano-biology 
Organisation Queen Mary University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution Expertise in the cell and developmental biology of cilia
Collaborator Contribution Expertise and facilities in Super-resolution microscopy
Impact outputs: (1) scientific data for publications that neither group could achieve by themselves (2) sharing of scientific ideas
Start Year 2015
 
Description Modelling nodal cilia 
Organisation University of Oxford
Department Department of Engineering Science
Country United Kingdom 
Sector Academic/University 
PI Contribution Ideas, measurements, discussion, comment and then we started the cycle all over again and again until we achieved the mathematical models.
Collaborator Contribution Expertise and microfluidics and computer modelling.
Impact Multi-disciplinary collaboration: Biology and geneticists. Engineering (fluid dynamics modellers) and computer modelling. Chen et al 2009, Chen et al 2011 Chen et al 2014
Start Year 2006
 
Description Pkd family antibodies 
Organisation Harvard University
Department Harvard Medical School
Country United States 
Sector Academic/University 
PI Contribution We are performing work and they are providing a unique reagent to us. We are therefore doing ALL of the work.
Collaborator Contribution Provision of a unique reagent to us.
Impact Collaboration has just started, so nothing as yet.
Start Year 2013
 
Description mouse models of primary ciliary dyskinesia (PCD) 
Organisation University of Southampton
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We identified the mouse model that we have analysed together with the team in Southampton. We have provided expertise, equipment and facilities for half of the analysis. We have also provided half of the intellectual input into this project.
Collaborator Contribution Analysis of a model phenotype at a level normally used for human diagnosis. Equipment, expertise and facilities as well as intellectual input have been provided by Southampton.
Impact identification of the first fully viable model model of PCD (Lucas, et al, 2012). identification of a novel form of PCD affecting nodal but not tracheal cilia (manuscript in preparation). multi-disciplinary: linking mouse genetics (MRC Harwell) and clinical science (National Diagnostic Service for PCD in Southampton)
Start Year 2007
 
Description BEAT-PCD 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A Europe-wide EU funded COST action to develop policy and research underpinning therpy for Primary Ciliary Dyskinesia (PCD).

I am running work-group 1, I am also one of the two UK management committee members
Year(s) Of Engagement Activity 2015
URL http://www.beatpcd.org/
 
Description BEAT-PCD training school 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact BEAT-PCD is a COST action combining clinicians, para-medical professionals, patients groups and basic scientists. The training school is aimed at primarily at trainees, to share and disseminate skills and expertise as well as to promote networking.

I chaired sessions at this meeting.
Year(s) Of Engagement Activity 2016
URL https://beat-pcd.squarespace.com
 
Description Cilia 2012 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact I helped to oraganise Cilia 2012, a conference for scientists, clinicians and for charities interested in ciliopathies (disease of cilia). Our first day was specifically aimed at bringing together patients and charities with researchers and clinicians in a social context. Over 300 people attended.

We have had excellent feedback and have already begun organisation for Cilia 2014 with the aim of a larger and longer conference.
Year(s) Of Engagement Activity 2012
 
Description Cilia 2014 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation workshop facilitator
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact As part of a small international committee I have organised an international conference on cilia and their role in health and biology. Nearly 400 attendees are expects at the Pasteur for the conference.

The session on the first day is explicitly for patients and patient representatives.

The conference is yet to happen, but we already have patient groups, French scientific funders and clinicians from around the world attending. Press coverage has been arranged. The abstracts of the conference will also be published.

we expect significant international scientific collaboration to emerge form this conference.
Year(s) Of Engagement Activity 2013,2014
URL http://www.cilia2014.org/
 
Description Diamond Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact MRC Harwell was at Diamond Light Source's open days this weekend, 14-15 March 2015, talking about the work we do at Harwell Campus and it's impact, including Dr Mary Lyon's work on X-inactivation.
Year(s) Of Engagement Activity 2015
URL http://www.har.mrc.ac.uk/news-events/news-archive/diamond-light-source-open-days
 
Description Hosting Palistinean medical student 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact We hosted a Palestinean medical student, passing on skills and ideas. We have encouraged his interest in science and made him well aware of British science.

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Year(s) Of Engagement Activity 2012
 
Description Hosting work experience students. 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact We annually host small groups of work experience students (usually still at school) in the lab. The PhD students are the primary hosts, but the entire group meets and talks to the students.

We provide actual experience of a research lab. Real people are here to reveal how unlike the Hollywood stereotypes real scientists are.

We also provide the students a window into a world class research environment.

This year (2014) one of the students decided that she wishes to pursue a career in research after seeing what is involved.
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014
 
Description MRC Harwell Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The MRC Harwell Open day. People from the area were invited into site to see and meet scientists and discover what happens on site.
Year(s) Of Engagement Activity 2016
URL http://www.har.mrc.ac.uk/news-events/news-archive
 
Description New York Times Article 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Front page, main story, of the New York Times science section. Originated from a review article I wrote for BMC Biology; the journalist contacted me, interviewed me as well as others in the field (many of at my suggestion). Assorted quotes in the article.

It is hard to assess the impact of a media article, but it is clear that scientific problem and its significant health impacts have reached a far wider audience.
The UK Primary Ciliary Dyskinesia (PCD) charity has used the article to inform patients and their parents of the links between cilia function and PCD.
Year(s) Of Engagement Activity 2013
URL http://www.nytimes.com/2013/06/04/science/growing-left-growing-right-how-a-body-breaks-symmetry.html...
 
Description PCD Patient group, 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact I attended the 2015 PCD Family Support Group meeting in Milton Keynes. During the day I spoke with patients and the parents of patients and we listened to presentations from professional practitioners and ptient representatives. PCD is a disease of immotile cilia and it gives rise to repsiratory problems that the patients are well versed in. However, 50% of the patients are situs inversus (their internal organs are left-right mirror reversed). I explained to the patients how this is controlled in the embryo (at just 3 weeks of age!) and how it requires motile cilia. I was suprised that not even the specialist consultant in the audience was fully aware of this. The talk was greeted with interested questions. I now hope that a proportion of PCD patients understand why they are situs inversus.
Year(s) Of Engagement Activity 2015
URL http://har.mrc.ac.uk/news-events/news-archive?page=1
 
Description PCD charity annual meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Presentation to the UK PCD charity annual meeting, comprising clinicians, nurses, physiotherapists, parents of patients, patients and researchers.

Continued contact with charity and clinicians. Some progress and publicity in the slow incremental realisation that heart disease should be monitored in PCD patients.
Year(s) Of Engagement Activity 2011
 
Description Scientific Advisory Bourd of the Ciliopathy Alliance 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact We have organised 2 international scientific conferences (Cilia 2102 and Cilia 2014) as well a ciliopathy patient days. We have made contact with and work with cilia organisations in other countries (Nordic, France and EU funded programmes). Our purpose and constitution can be read here:

http://www.ciliopathyalliance.org/about-us/purpose-constitution-and-constitution.html

Two international conferences. Out of these a unquantified number of collaborations have emerged.

My group has made contact with and worked with 3 others who we met at these conferences.
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014
URL http://www.ciliopathyalliance.org
 
Description Talk/discuss with residents of Richmond Retirement Village about our MRC research 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact A presentation-led discussion of the role of cilia in health, development and disease. Starting from the what a cell is and how it can be visualised, we travelled upwards in scale, to the tissues and organs that make up a body. This was provided the basis to discuss how smoking and viruses lead to similar symptoms. Approximately 40 residents were there and they asked questions both during and after the presentation; the audience included a retired teacher, nurse, physicist and slaughterman and the nature of the questiosn and dicsussion varied accordingly.
Year(s) Of Engagement Activity 2016
URL http://har.mrc.ac.uk/news-events/news-archive/richmond-village-talk-dominic-norris
 
Description Talking to local retirement community 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact I gave a presentation about aspects of our science to a retirement community. This comprised classical presentation as well as open discussion with the audience. Members of the audience was varied and included a retired slaughterman who related to discussion of body patterning (keft and right sides) and a retired physicist who knew the Harwell site.

The local organiser had been keen to get some science presentations as a way to engage more of the men in the community as they often do not attend such events.
Year(s) Of Engagement Activity 2016
URL http://har.mrc.ac.uk/news-events/news-archive?page=1
 
Description Teaching embryology course - India 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact A course to teach mouse genetics, embryology, and stem cell technologies held at the Institute for Stem Cell Biology and Regenerative Medicine in Bangalore, India. 150 people attended the scientific meeting (at which I presented) and 20 academics (students to lab heads) attended the two week practical course that we subsequently taught.

Continued conversation with Indian academia. Largely informal at present, but we now know each other and we know what skills both sides have.
Year(s) Of Engagement Activity 2013
URL http://instem.res.in/
 
Description U3A visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact visit by 50 university of the third age and probus members. These are primarily retirees from a broad cross section of society. There were questions and discussion over lunch.

I am unaware of any notable impact.
Year(s) Of Engagement Activity 2011