Investigating the molecular and cellular defects that lead to severe neural tube defects in the circletail mouse mutant

Lead Research Organisation: Medical Research Council
Department Name: Medical Research Council

Abstract

We are using mouse mutants with severe spina bifida to help understand the causes of this disorder.

We know that the brain and spinal cord form in the embryo from a structure called the neural tube. We also know that if the neural tube doesn‘t form correctly, then the individual has a neural tube defect such as spina bifida. But the reasons why neural tube formation is sometimes disrupted are only partly understood.

Studies of neural tube defects in human patients are very difficult, so we are using a mouse mutant that provides a model for the human defect. We can use the mouse mutant to investigate the precise defects in the embryo that lead to the severe spina bifida. We can study both the molecular and cellular processes in the embryos, over the time that the neural tube forms. We can also investigate the function of the mutant gene, to get a better understanding of what it does.

This will help to increase our understanding of what goes wrong in the embryos that develop neural tube defects. We hope that this information will help prevent neural tube defects from occurring in humans. By having a better understanding of the precise abnormalities that cause neural tube defects, it may be possible to design appropriate therapeutic remedies.

Technical Summary

The neural tube is the developmental forerunner of the brain and spinal cord, and is formed early in embryonic development. Abnormalities in neural tube formation result in neural tube defects (NTDs), which are one of the most common causes of birth defect. The most severe form of NTD, termed craniorachischisis, affects almost the entire brain and spinal cord, and is invariably lethal. This defect accounts for around 20% of all NTD cases, yet the molecular and cellular processes involved are poorly understood.

The aim of my proposal is to improve our understanding of the molecular and cellular basis of severe NTDs, in order to aid the development of preventive remedies. Direct analysis of human NTDs is very difficult, owing to practical and ethical constraints. However, the mouse provides an excellent model system with which to investigate the mechanisms involved. One mutant that exhibits the most severe form of NTD is circletail, and I have recently identified the gene disrupted in this mutant. My objective is to investigate the cellular and molecular basis of the neural tube defect in this mutant. This will greatly increase our understanding of the mechanisms involved in neural tube formation.

These objectives will be performed in collaboration with other internationally reknown scientists, who are researching complementary areas of investigation. Professor Andrew Copp is investigating the cellular defects in the loop-tail mutant, Dr Philip Stanier is screening for mutations in human patients with neural tube defects, and Dr Deborah Henderson is examining the heart defect in the circletail mutant.

Analysis of the cellular and molecular defects in circletail promises to generate significant new information on the mechanisms involved in neural tube defects. This will, in the long term, provide the opportunity to make significant advances in application to human preventive medicine, for instance by permitting genetic counselling and by suggesting appropriate therapeutic remedies.

Publications

10 25 50

 
Description Genetics Society Summer Studentship
Amount £2,000 (GBP)
Organisation The Genetics Society 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2006 
End 08/2006
 
Description Genetics Society Summer Studentship
Amount £3,000 (GBP)
Organisation The Genetics Society 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2010 
End 08/2010
 
Description Genetics Society Summer Studentship
Amount £2,000 (GBP)
Organisation The Genetics Society 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2007 
End 08/2007
 
Description Genetics Society Summer Studentship
Amount £3,000 (GBP)
Organisation The Genetics Society 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2009 
End 08/2009
 
Description Royal Society Research Grant
Amount £14,916 (GBP)
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 06/2011 
End 02/2013
 
Description Wellcome Trust vacation scholarship
Amount £1,400 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Vacation Scholarship
Sector Charity/Non Profit
Country United Kingdom
Start 04/2007 
End 08/2007
 
Title PCP mouse mutants 
Description Mouse mutants in genes that affect PCP signalling pathway 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? Yes  
Impact Several publications 16170314 17556662 18174466 19968984 18849982 
 
Description Analysis of eye defects in PCP mutants 
Organisation University of Sydney
Country Australia 
Sector Academic/University 
PI Contribution Sharing of reagents (mice and embryos)
Collaborator Contribution Sharing of ideas
Impact Publication: 19968984
Start Year 2008
 
Description Analysis of heart defects in PCP mutants 
Organisation Newcastle University
Department Institute of Human Genetics
Country United Kingdom 
Sector Academic/University 
PI Contribution Sharing of research materials including mutant mice and embryos; discussion of ideas.
Collaborator Contribution Intellectual input, sharing of reagents (antibodies)
Impact Publications: 17556662 18174466 Collaboration is on-going
 
Description Analysis of neuronal pathfinding defects in PCP mutants 
Organisation University of Missouri
Country United States 
Sector Academic/University 
PI Contribution Sharing of reagents (mice and embryos), discussion of ideas
Collaborator Contribution Sharing of ideas
Impact Paper submitted.
Start Year 2007
 
Description Genetic investigation of PCP mutants 
Organisation University College London
Department Institute of Child Health
Country United Kingdom 
Sector Academic/University 
PI Contribution Investigation into genetic interactions between mouse PCP mutants. I led this work and continued this after leaving the ICH labs. I co-wrote the paper.
Collaborator Contribution Initial experiments were conducted in labs of collaborator; co-wrote the paper; they paid the publication charge.
Impact PMID: 25128525