Award details

Principles of neural lumen morphogenesis in vivo

Reference	BB/K000926/1
Principal Investigator / Supervisor	Professor Jonathan Clarke
Co-Investigators / Co-Supervisors
Institution	King's College London
Department	Developmental Neurobiology
Funding type	Research
Value (£)	409,652
Status	Completed
Type	Research Grant
Start date	30/04/2013
End date	31/05/2017
Duration	49 months

Abstract

This proposal will significantly increase our understanding of a fundamental aspect of organ morphogenesis in a vertebrate embryo. Specifically we will determine the mechanisms by which cells are able to generate an epithelial tube from an initially solid neural primordium in the zebrafish embryo. We will address the roles of centrosome localisation in this process. We will assess whether centrosomes, microtubules and the polarity protein Pard3 operate in a self-reinforcing loop to establish and maintain the location for lumen assembly. We will assess the role of cell-cell interactions at the organ midline in determining the location of lumen assembly and we will assess the specific role of adherens junctions and the small GTPase RAB11A in this process. Finally we will apply our knowledge of these processes in the zebrafish embryo to the somewhat similar process of secondary neurulation in chick and mouse embryos. This will determine whether the principles that we have uncovered for the zebrafish system are also fundamental to neural lumen formation in the caudal segments of the spinal cords in animals that are more closely related to man.

Summary

During development of vertebrate embryos many of the internal organs are built with a hollow centre (called the lumen), for example the brain and spinal cord, the intestines, blood vessels, parts of the kidneys, etc. Lumen formation is thus a very fundamental process during embryo life. Our understanding of how this process works is very limited and in fact most of the information that we have is derived not from studying real embryos but from trying to study this process in cells and tissues grown under special conditions in plastic petri dishes. Such studies on cells outside the real embryos is valuable but is necessarily not fully representative of the normal environment and processes that actually take place in real animals. We are using a simple animal system to study lumen formation in real embryos. For this we use fish embryos that have the huge advantage of being transparent and therefore the whole embryo can be placed under a microscope in order for the behaviour of individual cells to studied at high resolution in their natural environment. The main experiments we will carry out are designed to tell us whether a small component of all cells called the centrosome is a key feature in organising the process of lumen formation in the zebrafish brain and spinal cord. Our previous experiments have suggested that the centrosome is a key player in this process, but we have not previously been able to test this idea experimentally. The second aim of our work is designed to test the idea that the principles we have learnt and are learning from our studies of fish brain and spinal cord development are also important during spinal cord development in other animals more closely similar to humans. For this we will study the development of the lower end of the spinal cord in mice embryos and chicken embryos. It is already established that there are some similarities in the basic organisation of cells during lumen formation in fish spinal cord and mouse and chick spinal cord development, but there is almost no information for mice and chick at the molecular level (i.e. what genes and proteins are involved). Our work in fish gives us a good idea of which genes and proteins might be important in mice and chick and we will therefore study these in detail in order to better understand these fundamental processes in vertebrate embryos. In the long term our work will be relevant to human tissue repair and replacement as our knowledge will help rebuild damaged tissues either by encouraging repair in a patient or by engineering a complex tissue first in a petri dish in order for that tissue then to be transplanted into a patient whose own tissue or organ has been damaged.

Impact Summary

Who will benefit and how? Our principle impact will undoubtedly be on the academic community interested in how embryos generate and shape organs. Our work will also have relevance to tissue engineering and therefore potentially institutions interested in developing system for repair and replacement strategies to treat damaged and diseased tissues and organs. We intend our work will lead to future interactions between our lab and tissue engineering labs where we hope to be able to use our knowledge derived from the current studies to devise strategies for building epithelial tubes in vitro. With this aim we are beginning a collaboration with tissue engineers in Karlsruhr Institute of Technology in Germany that we hope will be funded by an European Research Council Synergy grant. In the longer term this work could thus impact on the nation's health. Since we work in a University our work also has considerable impact on the student community. We are fully engaged in research-led teaching both through lectures and seminars to undergraduates and through hosting laboratory based experimental research projects for undergraduates. We also host work experience school children in the summer months and we will continue to do this as a method of enriching the experience of pre-university students. We believe our continued successful engagement in research significantly enhances both the excitement and inspirational quality of our teaching. Our work thus has an indirect impact on the undergraduate student experience. We are also involved in outreach work with local schools. Clare Buckley is a STEM Ambassador with STEMNET and the supportive nature of our department has enables her to run 'Brain Games' workshops at Petchey Academy, Hackney with GCSE students as well as organising school visits to the lab and participating in several KCL 'scientists in sport' school workshops. Our research forms the basis of much of this outreach activity. We give school students the chance to see how basic research can be applied to biological problems with a broad relevance; something that they would not usually be exposed to at school.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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