Heart disease, Primary Ciliary Dyskinesias, Left-Right patterning, cilia, development

Lead Research Organisation: MRC Mammalian Genetics Unit


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Technical Summary

While externally mirror symmetrical between left and right the mammalian body shows left-right (L-R) asymmetry in the placement and patterning of organs and vasculature. While complete inversion of sidedness (situs inversus) is viable, incomplete conversions (situs ambiguous) carry serious health implications. The humans conditions polyasplenia, primary ciliary diskinesias (PCD) and Kartagener syndrome, cause situs inversus and situs ambiguous. A significant level of congenital heart disease (CHD) is associated with these defects and it has become obvious in recent years that CHD can be the sole manifestation of low level L-R patterning defects. Situs defects are also associated with extrahepatic biliary atresia and polycystic kidney disease; these too are associated with CHD. Understanding the genetics of L-R development will therefore aid understanding of not merely situs defects but of CHD, PCD and cystic kidney disease.
During mammalian development, L-R symmetry is thought to be broken at the embryonic node when motile cilia create a leftward flow of liquid. Although models to explain this have emerged, it remains unclear how the flow is perceived by the developing embryo. Positional information is then communicated, by an unknown mechanism, from the node to the left lateral plate, activating Nodal which in turn activates Pitx2 expression. However, Pitx2 null embryos do not loose all aspects of left sidedness, making it clear that additional uncharacterised signals distinguishing the left and right sides of the embryo.
We have identified a gene novel to L-R determination, expressed in the left lateral plate and on the right side of the node. Preliminary data suggests its expression is independent of Nodal and Pitx2. It is possible that this gene may be responsible for aspects of "leftness" still present in Pitx2 null embryos. We aim to investigate both the function and control of this gene.
We have identified 11 mutants affecting L-R determination; seven appear novel. We will characterise the events occurring as these mutants attempt to establish L-R asymmetry, with particular attention on events at the node. We will refine map positions for these mutants and identify the genes mutated. We will integrate this information with existing models of L-R development and with the network of genes controlling L-R development. We will refine, develop and test models emerging from our results. Further, through collaboration, we will screen cardiac patients for defects in the genes implicated by this work.


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Title mouse models of PCD 
Description Using a genetic screen we have identified mouse mutants affecting left-right patterning. subsequent work has demonstrated that some of these mutants also model primary cilary dyskinesia (PCD) 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2012 
Provided To Others? Yes  
Impact This provides tools with which we and other groups can investigate PCD and possible treatments. 
Description Cilia 2016 
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 This is the bi-annual European Cilia conference. We have managed to get sponsoship from EMBO for cilia2016

Organisation started in 2015 and the conference will be in 2016.

A worldwide audience in involved and we expect more than 400 poeple to attend and many more to be influenced back in the labs that they travel from. On the basis of Cilia 2014 we expect worlwide attendence.
Year(s) Of Engagement Activity 2015,2016
URL http://events.embo.org/16-cilia/
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 School visit 
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 1 day spent in the class room presenting to 4 different classes. The school in question invites 16 scientists into their classrooms as part of a "science week" every year.

Year(s) Of Engagement Activity 2009
Description Utrecht students 
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 Public/other audiences
Results and Impact presentation to Students from Utrecht on the use of mouse models in research

not evaluated
Year(s) Of Engagement Activity 2011