Heart disease, Primary Ciliary Dyskinesias, Left-Right patterning, cilia, development
Lead Research Organisation:
MRC Harwell Institute
Abstract
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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.
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.
Organisations
People |
ORCID iD |
Publications
Stevens J
(2010)
Analysis of the asymmetrically expressed Ablim1 locus reveals existence of a lateral plate Nodal-independent left sided signal and an early, left-right independent role for nodal flow.
in BMC developmental biology
Cruz C
(2010)
Foxj1 regulates floor plate cilia architecture and modifies the response of cells to sonic hedgehog signalling.
in Development (Cambridge, England)
Field S
(2011)
Pkd1l1 establishes left-right asymmetry and physically interacts with Pkd2.
in Development (Cambridge, England)
Goggolidou P
(2014)
Atmin mediates kidney morphogenesis by modulating Wnt signaling.
in Human molecular genetics
Lucas JS
(2012)
Static respiratory cilia associated with mutations in Dnahc11/DNAH11: a mouse model of PCD.
in Human mutation
Chen D
(2009)
The active and passive ciliary motion in the embryo node: a computational fluid dynamics model.
in Journal of biomechanics
Chen D
(2011)
Ciliary behaviour and mechano-transduction in the embryonic node: computational testing of hypotheses.
in Medical engineering & physics
Ashrafian H
(2010)
A mutation in the mitochondrial fission gene Dnm1l leads to cardiomyopathy.
in PLoS genetics
Guzman-Ayala M
(2009)
Graded Smad2/3 activation is converted directly into levels of target gene expression in embryonic stem cells.
in PloS one
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. unknown |
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 |